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Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Zhou Chen, Fangfang Han, Yan Du and 2 more

Signal Transduction and Targeted Therapy · 2023 · Review · CC BY

Abstract

Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 15, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Cancer occurrence is markedly associated with increasing age, as patients aged over 60 years are more than twice as likely to develop invasive cancers than younger patients. The World Health Organization (WHO) estimates that by 2050, the proportion of the world population aged over 60 years will have increased from 12 to 22%, totaling over 2 billion individuals. In the United States, cancer is the second leading cause of death after heart disease. In humans aged over 60 years, cancer is the leading cause of death. Due to the aging of the global population, cancer has become a global public health issue, with a massive economic burden and complex treatment challenges. The distribution of oxygen partial pressure in tumor tissues is of particular interest to radiologists because the radiosensitivity of tumor tissues depends on the tissue O2 tension. Tumor cells living under adequate hypoxic or hypoxic conditions are relatively resistant to radiation.

2In 1953, Gray et al. found that well-oxygenated tumor cells responded trice as well to radiotherapy than hypoxic cells. Tumor hypoxia was first proposed in 1955 by Thomlinson et al. in a study of tumor tissues from patients with lung cancer, and scientists have confirmed, through over 60 years of clinical and experimental evidence, that the hypoxic state is a widespread trait in a variety of solid tumors. The expression of key genes such as hypoxia-inducible factors (HIFs) and their various subunits, as well as the molecular regulatory mechanisms, were also explored under hypoxic conditions.– William Kaelin, Peter Ratcliffe, and Gregg Semenza have been awarded the 2019 Nobel Prize in Physiology or Medicine for the contributions of several scientists who have discovered how human and animal cells sense and adapt to oxygen supply (Fig. 1). Hypoxia is present in 90% of solid tumors, which is considered a hallmark of cancer., It is difficult to determine the hypoxic state in tumors due to variations in oxygen content between tissues, as well as differences in tumor size and measurement methods, and tissue oxygenation is highly variable, also within the same organ. However, the available results indicate that the measurement of tumor partial pressure of oxygen (pO2) in patients (polarographic technique) has demonstrated the presence of low values (<10 mmHg) in several different tumor types, including pancreatic cancer, head and neck tumors, breast cancer, cervical cancer, and melanoma.– Intra-tumor hypoxia is linked to decreased disease-free survival outcomes in several cancers including prostate, cervical cancer, and head and neck squamous cell carcinoma (HNSCC).– The hypoxic environment alters the expression levels of genes that modulate metabolism and other processes. Moreover, hypoxic signaling interacts with other cellular pathways to alter cancer cell malignant behaviors and is closely associated with cancer cell proliferation, migration, invasion and angiogenesis, and affects cancer treatment outcomes. This article focuses on the unique hypoxic microenvironment in cancer, the possible mechanisms by which cells undergo transformation and malignancy, and the potential applications of these aspects.

Factors contributing to hypoxia in cancer

3The vasculature ensures the presence of tissue oxygen and energy substances. Vasculature endothelial cells (ECs) of cancer tissues or pre-neoplastic tissues are exposed to harmful substances, including various high-risk carcinogenic factors, such as drugs, carcinogens, pathogenic microorganisms, and the uniquely acidified tumor microenvironment (TME), which damage the shapes of ECs (for example, edema), resulting in dysregulated functions of cancer vasculature. Cancer cells are characterized by high proliferative rates and active metabolism; they also consume high amounts of energy to support their increased cell proliferation and growth rates. When metabolic oxygen demands exceed supply, the oxygen-deficient areas of cancer cells are exacerbated and they are change their metabolism. Abnormal vascular structures and patterns that are due to dysregulated angiogenesis contribute highly to hypoxia. Although the expression of erythropoietin (EPO) and angiogenic factors are increased under hypoxic conditions, which promote the proliferation of vascular ECs, the arrangement is disorganized and non-functional vessels form.– Cancer rapidly grows such that the cancerous area is often deficient of vasculature and becomes hypoxic. In the TME, chronic hypoxia occurs as the distance of cancer cells from blood vessels increases and O2 diffusion decreases, which has been further validated in a mouse model of breast cancer. Hypoxia can occur in tissues more than 100–200 µM from a functional blood supply, a phenomenon that is prevalent in solid tumors. Additionally, using a model of rat brain gliom, Julien et al. found that the peritumor vasculature is vaso-responsive to hypoxia through alpha-smooth muscle actin, which can further exacerbate hypoxia in areas of tumor tissue with principle blood vessels. Some blood vessels become abnormal and malfunction, resulting in hypoxia. Non-cancer components and functions are greatly altered, including the activation and proliferation of stromal cells (for example, stellate cells and cancer-associated fibroblasts) and increased stromal components (for example, fibrin),, leading to remodeling of cancer morphology, such as vascular compression. This can result in impaired circulation and inadequate oxygen supply, further leading to thrombosis and increased tissue hypoxia. Physiological effects of various factors, such as magnesium, change with the changing hypoxic environment. Under normoxic conditions, magnesium stimulates angiogenesis, whereas under hypoxic conditions, Mg inhibits angiogenesis. The above factors can cause hypoxia in the TME (Fig. 2).

4Hypoxic factors are prevalent in most solid tumors. Some tumors contain transient hypoxic cells, others contain chronic hypoxic cells, and others contain both components. This may include three different cell populations. The first type is chronically hypoxic cells. If left in situ, the cells die. These “doomed” cells survive alone after the necessary excision in the cell survival assay and does not affect the response of the tumor when left in situ, which is considered the main cause of cell necrosis in the central region of solid tumors. The second type is the chronically hypoxic cells that are viable if left in situ. These cancer cells are stimulated by hypoxia to promote proliferation, alter gene expression, and enhance cellular drug resistance and radioresistance.,– The third type is transient hypoxic cells, which are expressed closer to functional blood vessels, where the duration of hypoxia is short. Based on current evidence, tumor cells adapt to hypoxia by altering their signaling pathways. Hypoxia promotes malignant behavior of cancer cells, including proliferation, migration, infestation and epithelial-mesenchymal transition (EMT), and enhances immunotherapy, chemotherapy, and radiotherapy tolerance.

Hypoxia and genomic damage

5Hypoxia damages the cellular genome and drives carcinogenesis. In in vitro and in vivo hypoxic cancer models, gene mutation frequencies of hypoxic cancer cells were increased by 2- to 5-fold.– In tissue culture and animal models, gene amplification and mutations were associated with induction of DNA strand breaks during hypoxia, including DNA double-strand break (DSB) and single-strand break (SSB).– In addition, hypoxic conditions (<5%) could improve the efficiency of induced pluripotent stem cell (iPSC) generation from mouse and human somatic cells. The hypoxic signaling microenvironment maintains stem cell self-renewal by facilitating the reprogramming process.– The extrapolation of these iPSC studies provides insight into cancer stem cell (CSC), which can also exist in hypoxic ecological niches. Hypoxia is known to promote and maintain CSC phenotypes. CSCs are thought to have the potential to form tumor that will develop into cancer, especially when they metastasize with the cancer and will give rise to novel sources of cancer. Both mutation due to cellular genomic damage and the maintenance of CSCs are closely related to the production of large amounts of reactive oxygen species (ROS) under hypoxic conditions., The aforementioned mutations and breaks stimulate expression of oncogenes, thereby inducing the formation of cancer cell variants that have the potential to metastasize and grow.

Hypoxia and genetic repair

6Hypoxia activates ataxia telangiectasia mutated (ATM) and ATM and RAD3-related (ATR) checkpoints. ATM and ATR belong to the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family and are the main members of the DNA damage checkpoints. They are activated by different types of DNA damage and regulate cell cycle checkpoints by phosphorylating their corresponding downstream proteins (CHK1 and CHK2). The specificities and functionalities of ATM and ATR during DNA damage differ, with ATM being mainly involved in DNA DSB repair. After hypoxia-mediated DNA double-strand breaks, the MRE11-RAD50-NBS1 (MRN) complex activates ATM and is autophosphorylated at serine 367 (ser367), serine 1893 (ser1893), serine 1981 (ser1981), and serine 2996 (ser2996), thereby inducing MRE11-RAD50-NBS1 (MRN) complex-associated recruitment of various complex phosphorylation cascades, such as p53 (cancer suppressor), CHK1, and CHK2, to the DNA DSB sites. These effects can be blocked by the inhibition of CDK2 activity. During G1/S or G2/M cell cycle progression, cells have more time to repair DNA damage before entering mitosis. ATR kinase phosphorylates p53 and CHK1 under extreme hypoxia (oxygen concentration <0.02%). Once ATR is activated, it phosphorylates and inactivates CDC25 by phosphorylating CHK1 and CHK2, thereby resulting in failure to activate CDK2. These lesions can block G1/S or G2/M cell cycle progression by phosphorylating CDK1.– In glioma mice models, inactivation of the ATM/CHK2/p53 pathways promoted cancer formation. Hypoxia cannot induce G2 arrest in CHK2-deficient cells, but these cells can undergo apoptosis under hypoxia., Persistent hypoxia enhances DNA misreplication and DNA strand breaks, resulting in mutant cell phenotypes. Non-homologous end joining (NHEJ) and homologous recombination (HR) regulate the repair of human DNA DSB.– DNA DSB are the most severe and extensive types of damage; HR can accurately repair these damages, especially in the S/G2 cell cycle stage. NHEJ is the simplest mechanism of DNA DSB repair and can act in all cell cycle phases, except for the M phase. In hypoxic conditions, HR repairs the lesions less frequently, whereas NHEJ activities are unaffected., The mismatch repair (MMR) pathway can also be deregulated under hypoxic conditions. MMR is a DNA repair pathway that targets replication-related errors and primarily functions to correct the misintegration of nucleotides during DNA synthesis, thereby preventing permanent DNA damage in dividing cells. Hypoxia decreases the expression of MLH1 and MSH2, which induces mutations and dinucleotide repeat instability. These pathways may lead to sustained damage to intracellular RNA, resulting in cell transformation, including carcinogenesis.,

HIFs and cancer cells

7To survive under hypoxic conditions, cancer cells reprogram their metabolism, protein synthesis, and cell cycle progression through the synergy of transcription factors. One of the main reasons why cancer cells can survive in hypoxic environments is the activation of HIFs, which reprogram metabolism, protein synthesis, and cell cycle progression., The HIF family has two distinct subunits: α (HIF-1α, HIF-2α, and HIF-3α) and β (HIF-1β). HIF-1α is widely expressed in all body tissues, whereas HIF-2α and HIF-3α only occur in specific tissues. HIF-1α is an oxygen-unstable protein that becomes stable in response to hypoxia, iron chelators, and divalent cations., In cell culture under hypoxic conditions, HIF-1α mRNA levels did not change, but HIF-1α protein levels increased. HIF-1β is constitutively expressed in mammalian cells under normoxic conditions. Owing to the presence of the oxygen-dependent proline hydroxylase family (PHD), under sufficient oxygen conditions, the HIF-α protein is hydroxylated and interacts with von Hippel-Lindau tumor suppressor protein (pVHL) to promote HIF-1α ubiquitin-proteasomal degradation.– Ectopic expression of PHD1 inhibited HIF-1α and suppressed tumor growth. However, under hypoxic conditions, enzymatic activity of PHD is inhibited, preventing HIF-α hydroxylation and ubiquitin-mediated proteasomal degradation, leading to abnormal accumulation of HIF-α in cells. Significantly elevated mRNA of HIFs was detected after 1 h at O2 concentrations <10%. In addition, high expression of the CSN subunit CSN5 stabilizes HIF-1α aerobically by inhibiting HIF-1α prolyl-564 hydroxylation. Also under normoxic conditions, elevated intracellular ROS induced sustained expression of HIF-1α protein. The accumulated HIF-1α binds to HIF-1β and enters the nucleus to bind the hypoxia response element (HRE) in the promoter region of the target gene to reduce cellular oxygen consumption., HIF-3α exerts the opposite effects in cancer cells by impairing angiogenesis, proliferation, and metabolism. Biologically, HIF is regulated by multiple signaling pathways, including the PI3K-mTOR signaling pathway;– JAK-STAT3 signaling pathway; NF-κB pathway;, mitogen-activated protein kinase (MAPK) pathway;, Wnt/β-catenin pathway; Notch pathway; cancer suppressor gene deletion, such as p53, phosphatase, and tensin homolog (PTEN); and IDH1-R132H-FAT1-ROS-HIF-1α signaling pathway (Fig. 3). Mechanistically, HIF regulates cancer cell growth by regulating genes encoding enzymes that hydrolyze sugars, angiogenic signaling genes, and apoptosis/stress response genes.

Hypoxia and cancer cell behaviors

8Among various cancers, patients whose primary cancers are hypoxic at diagnosis are more likely to have local recurrence and metastatic site recurrence, regardless of whether the initial treatment is surgery or radiation therapy. Cancer patients with conditions such as anemia or chronic obstructive pulmonary disease tend to have poorer prognostic outcomes and may have cancer-related hypoxia, at least in part, owing to increased propensity to develop metastatic disease., Young et al. reported that exposure of cancer cells to a hypoxic environment in vitro or in vivo enhanced spontaneous metastasis., Similar results were obtained in mouse models of fibrosarcoma and cervical cancer., To an extent, hypoxic conditions eliminate tumor cells that are sensitive to hypoxia, and the surviving tumor cells adapt to hypoxia through their own molecular transformation. Several early experiments have supported that hypoxia-induced increases in HIF-1α expression can drive the metastatic phenotype by upregulating genes involved in the metastatic cascade, such as urokinase-type plasminogen activator receptor (uPAR), matrix metalloproteinase 1 (MMP1), chemokine receptor 4 (CXCR4), osteopontin (OPN), known as secreted phosphoprotein 1 (SPP1), lysine oxidase (LOX), interleukin 8 (IL-8), and vascular endothelial growth factor (VEGF).– Hypoxia-exposed cancer cells are selective for the loss of p53 functions or increased expressions of the p53 negative regulator (MDM2), leading to increased resistance to apoptosis and increased metastasis., Other experiments did not find correlation between hypoxia and p53. HIF-1α binds and activates the MAX interactor-1 (MXI1), a repressor of the c-MYC transcriptional activity, and reduces the expressions of c-MYC, a factor that encodes mitochondrial DNA replication and promotes mitochondrial biogenesis,, which inhibits cancer cell mitochondrial biogenesis and cellular oxygen consumption, resulting in cancer growth and survival in a hypoxic environment. Unfortunately, MYC overexpression occurs in 70% of human cancers. HIF-2α promotes the expressions of the MYC and E2F target genes, which are involved in lipoprotein metabolism and ribosome biosynthesis. Conversely, MYC maintains cancer stem cell self-renewal properties by selectively binding the promoter and activating the HIF-2α stemness pathway. Both HIF-1α and MYC can enhance the glycolytic pathway and drive cancer proliferation and progression., Under hypoxic conditions, HIF-1α directly and positively regulates ephrin A3 (EFNA3) expressions. Ephrin type-A receptor 2 (EphA2), a key functional mediator downstream of EFNA3, promotes sterol regulatory element binding protein (SREBP1) maturation, which drives the self-renewal, proliferation, and migration of hepatocellular carcinoma (HCC) cells. Under the effects of HIF-1α, prostate intraepithelial neoplasia (PIN) cells highly express transglutaminase 2 (TGM2) and exhibit impaired androgen signaling, enhancing malignant progression. In addition, some factors, such as Orai1; phospholipase D2 (PLD2); annexin A3 (ANXA3); CXCR4; cysteine-rich protein 2 (CSRP2); hematopoietic pre-B cell leukemia transcription factor-interacting protein (HPIP); twist family bHLH transcription factor 2 (TWIST2); and non-coding RNAs, such as long-stranded non-coding RNA (lncRNA) PVT1, lncRNA-GAPLINC, and LncRNA-MTA2TR; and microRNAs, such as miR-525-5p, miR-301a-3p,, and miR-141-3p, play important roles in regulating hypoxia-induced cancer cell proliferation, migration, invasion, and angiogenesis in the TME under hypoxic conditions (Table 1).

Hypoxia and glycolysis

9The majority of cancer cells increase glucose uptake and rely on glycolysis through a phenomenon known as the “Warburg effect”.,, The “Warburg effect,” activated by MYC and HIF-1 in response to growth factors and hypoxia, is aerobic glycolysis with the purpose of meeting the nutrient and energy requirements for rapid genome replication. HIF-1α is the main transcription factor that promotes Warburg-like metabolism.,, HIF-1α stimulates various enzymes such as glycolysis regulator phosphoglycerate mutase 1 (PGAM1), pyruvate kinase M (PKM), recombinant phosphoglycerate kinase 1 (PGK1), lactate dehydrogenase A (LDHA), lactate dehydrogenase C (LDHC), and lactate dehydrogenase-5 (LDH-5) to induce anaerobic metabolic shifts that lead to energy production.– HIF-2α promotes MYC target gene expression and enhances constitutive expression of LDHA., In addition, HIF-1α inactivates pyruvate dehydrogenase (PDH) by activating pyruvate dehydrogenase kinase 1 (PDK1), which in turn fails to convert pyruvate to acetyl-CoA, preventing the entry of pyruvate into the tricarboxylic acid (TCA) cycle. This leads to lactate accumulation that increases intracellular adenosine triphosphate (ATP) levels and reduces hypoxic ROS production, thus rescuing these cells from hypoxia-induced apoptosis.–

10Lactate and H+ generated by glycolysis cross cell membranes through monocarboxylate transport proteins (that is, MCT1/4), sodium hydrogen (Na+/H+) exchanger (NHE) isoform 1 (NEH1), and carbonic anhydrase 9 (CAR9), contributing to cellular pH homeostasis and driving cancer proliferation and progression.,,– Interestingly, cancer cells relying on MCT1 can autonomously consume lactate, predominating as a carbon source for the TCA cycle. Pyruvate is converted from glycolysis to lactate, while lactate is used as a respiratory fuel to support the energy and synthetic functions of the TCA cycle, which is significant for the proliferation of cancer cells.

Hypoxia and lipid metabolism

11Lipid metabolism confers aggressiveness to malignant tumors by promoting membrane formation, energy storage, and production of signaling molecules, as well as by providing an important source of ATP production through fatty acid oxidation (FAO). Lipids are composed of triglycerides and lipoids such as phospholipids, cholesterol, and cholesteryl esters. Lipid metabolism involves lipid synthesis, storage, and degradation. Fatty acid (FA) are essential for lipid biosynthesis and are dependent on the activities of fatty acid synthase (FASN), adenosine triphosphate citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturases (SCD). Endogenous FA biogenesis constitutes an oncogenic stimulus that drives malignant tumor progression. HIF-1 significantly upregulates sterol regulatory element-binding protein (SREBP)-1, a major transcriptional regulator of the FASN gene, which in turn promotes FASN expression. Activation of FASN under hypoxic stress promotes de novo lipid synthesis and cell survival., ACLY is the main enzyme responsible for the production of acetyl-CoA in the cytosol in most tissues, and its product, acetyl-CoA, is used to provide a variety of biosynthetic pathways, including lipid synthesis and cholesterol synthesis. ACLY is responsible for catalyzing the conversion of citrate and CoA to acetyl-CoA and oxaloacetate. Studies have suggested that miR-27 and miR-195 are also upregulated in hypoxia-induced cardiomyocytes, suppressing the expression of ACLY and ACC., The mechanism of ACLY regulation in tumor cells under hypoxic conditions is still unclear. ACC (including ACC1 and ACC2) is the rate-limiting enzyme in the FA synthesis pathway. Under hypoxic conditions, the inhibition of ACC1 and ACLY increases the level of α-ketoglutarate by decreasing the level and activity of ETV4 to prevent hypoxia-induced apoptosis. ACC2 is hydroxylated by PHD3, which inhibits FAO. Under hypoxic conditions, PHD3 loss reduces ACC2 hydroxylation and promotes FAO to provide energy., SCD is a membrane protein of the endoplasmic reticulum that catalyzes the formation of monounsaturated FA (MUFA) from saturated FA, promotes tumor progression, and is associated with tumor recurrence and poor prognosis.– The main products of SCD are palmitoleic and oleic acids, providing key substrates for the production of complex lipids such as triglycerides, phospholipids, and cholesterol esters. Intermittently hypoxic mouse hepatocytes upregulate SCD1 mRNA and protein by increasing SREBP-1 and serum monounsaturated FAs. HIF-1/2α promotes the progression of clear cell renal cell carcinoma by inducing SCD1 expression.,

12Glutamine is the most abundant amino acid in blood and has been identified as necessary to promote mitochondrial metabolism in rapidly dividing cancer cells. HIF-1 activation leads to a significant decrease in the activity of the mitochondrial enzyme complex α-ketoglutarate dehydrogenase (αKGDH), which inhibits the oxidation of α-ketoglutarate (α-KG) as a product of the metabolic conversion of glutamine to succinate, its reductive carboxylation to isocitrate by isocitrate dehydrogenase (IDH), and then oxidation to citrate., HIF promotes glutamine-derived citrate conversion to cytoplasmic acetyl-CoA, which increases FA synthesis.

13Interestingly, the lipid catabolic metabolism also contributes to cancer metastasis. Under hypoxic conditions, the main enzymes associated with lipid catabolism in tumor cells are phospholipase A2 (PLA2), phospholipase D (PLD), and carnitine palmitoyltransferase 1 (CPT1). PLA2 catalyzes the hydrolysis of glycerophospholipid (GPL) to produce lysophospholipid (Lyso-PL). Lysophosphatidic acid stimulates PLA2 phosphorylation in a HIF-1α-dependent manner, promoting ovarian cancer cell metastasis in vivo. PLD hydrolyzes phosphatidylcholine (PC) to produce phosphatidic acid (PA). Activation of the PLD1/AKT pathway increases proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) in HCC. HIF-1α up-regulates the expression of PLD2 in colon cancer cells under hypoxic conditions. In turn, PLD regulates HIF-1α at the translational level in a vHL non-dependent manner in renal cancer cells., Prostate cancer cells with CPT1A overexpression showed enhanced proliferation, stemness, and tumor growth compared to controls under hypoxic conditions, mildly affecting the angiogenic response. Breast cancer cells expressing CPT1C showed increased FAO, ATP production, and resistance to glucose deprivation or hypoxia. However, experimental results have shown that HIF-1α and HIF-2α inhibit CPT1A expression in clear cell renal cell carcinoma, reduce FAs transport into mitochondria, and result in FAs being stored in lipid droplets. Compared with normal tissues, CPT1A expression and activity were reduced in clear cell renal cell carcinoma patient samples. Similar results were observed in gastric cancer tissue. Cancer cells optimize their requirements for rapid growth and aggressive progression by fine-tuning the lipid anabolic/catabolic switch. However, the dominant role of this fine-tuning mechanism remains unclear. Glucose and lipid metabolism in cancer cells under hypoxic conditions is showed in Fig. 4.

Hypoxia and angiogenesis

14In the early 1970s, Folkman et al. popularized the concept of tumor angiogenesis, presenting that growing tumor cells must replenish their own blood supply to maintain oxygen and nutrients. The accumulated experimental results have shown that hypoxia favors EC proliferation and migration. Deletion of p53 in cancer cells increases HIF-1α levels and enhances transcriptional activation of HIF-1-dependent VEGF and erythropoietin (EPO) in response to hypoxia, thus promoting EC proliferation, migration, and angiogenesis.,,– Hypoxia-induced E74-like ETS transcription factor 3 (ELF3) mediates increased secretions of insulin like growth factor (IGF1) and VEGF to promote EC proliferation, migration, and angiogenesis. HIF-1α mediates β-adrenergic receptor pro-angiogenesis.,– In addition, hypoxia stimulates the production of hyaluronic acid (a major component of the vascular basement membrane) and hyaluronidase activity, thus possibly promoting angiogenesis as a compensatory mechanism for hypoxia. However, tumor angiogenesis is not necessarily equivalent to tumor blood supply, as the discontinuous basement membrane of immature neovascularization allows for plasma and protein extravasation, further elevation of intra-tumor interstitial pressure, persistent vascular collapse, and poor nutrient delivery. In addition, some tumors exhibit an inability to maintain vascular survival, a condition that explains the well-formed, invasive peripheral and centrally necrotic hypoxic regions found in several highly angiogenic tumors. Therefore, in most cancers, despite the high vascular density, the neointima that forms are typically twisted and dysregulated, not functional for blood transport, and less efficient in oxygen and nutrient transport as well as drug delivery.–, Traditional anti-angiogenic strategies have attempted to reduce the vascular supply to the tumor, but their success has been limited by insufficient efficacy or the development of drug resistance. Normalization of vascular abnormalities may still be beneficial for tumor treatment with the available therapies.

Hypoxia and immune tolerance

15Cancer immunotherapy has emerged as a promising strategy for the treatment of various cancers by stimulating the immune system of the patient. Programmed death receptor 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA4) blocking antibodies, which are drugs approved by the Food and Drug Administration (FDA), have shown promising results in clinical trials for the treatment of various cancers. For some cancers, including breast, pancreatic, colorectal, and prostate cancers, a high proportion of non-responders has been reported, one of the main causes of which is hypoxic stress. Hypoxia-induced HIF-1α can promote programmed death ligand-1 (PD-L1) expression in cancer cells and suppress immune effects. Moreover, hypoxia plays a central role in cancer progression and resistance to therapy by promoting various changes in the biology of stromal cells in the TME, including immune cells. The main mediators of transcriptional hypoxic responses are HIF-1α and HIF-2α, which induce gene transcription, leading to hypoxic responses, and are involved in the regulation of carcinogenesis as well as stromal responses. HIF-1α has important functional roles in both innate and adaptive immune cells, including macrophages, neutrophils, dendritic cells (DCs), and lymphocytes. HIF-2α has been associated with macrophage NO homeostasis. In addition, deletion of the aryl hydrocarbon nuclear translocator (ARNT)/HIF-1β gene in CD8+ T cells impairs the expression of cytolytic effector molecules, including perforins and granzymes.

Hypoxia and T cells

16A distinctive feature of T cells is the markedly increased glucose uptake through glucose transporter 1 (GLUT1) as they respond to immune challenges and differentiate into cytotoxic T lymphocytes (CTLs)., Activated lymphocytes generate energy largely through upregulation of aerobic glycolysis. Glycolysis requires T cells to activate and maintain the expression of glycolytic enzymes, for example, pyruvate kinase (PK) and lactate dehydrogenase (LDH), and also requires T cells to maintain high levels of glucose uptake by maintaining the expression of glucose transporters. Relatively high levels of exogenous glucose are required to maintain the CTL transcriptional program., HIF-1α enhances the glycolytic activity of but not HIF-2α. Elevated HIF-α expression of T cells in hypoxic environments is regulated by multiple pathways, including the PI3K/mTOR-dependent pathway, protein kinase C (PKC) and Ca2+/calcineurin, STAT3 dependence, NF-κB, MAPK pathways, and T cell antigen receptors (TCRs) (Fig. 5). Deletion of VHL impairs HIF-1α and HIF-2α degradation, which significantly elevates the expression of various members of the CTL secretory granzyme family, including perforin and tumor necrosis factor α (TNF-α), thereby sustaining CTL effector functions. In natural killer (NK) cells, APOBEC3G triggered site-specific editing of C-to-U RNA under hypoxia. These effects have been shown to occur independently of HIF-1α, suggesting the existence of other potential regulatory mechanisms. HIF-α activities in CD8+ tumor-infiltrating lymphocytes (TILs) promote their accumulation and anticancer activities, as well as the production of interferon-gamma (IFN-γ) by CD4+ T cells. HIF-1α deficiency attenuates the ability of some CD8+ T cells to cross the endothelial barrier and reduces the abundance of infiltrating CD8+ T cells in the TME. This is because VEGF-A facilitates the recruitment of immune cells. VEGF-A derived from T cells promotes VE-cadherin endocytosis in ECs, causing EC adhesion junction disruption and vascular homeostasis imbalances, resulting in higher expression of the adhesion molecule (VCAM-1), which mediates immune cell adhesion to the vascular endothelium. This finding suggests that T cell-derived VEGF-A affects T cell homing through the endothelial barrier. VEGF-A levels in cancers are inversely correlated with CD8+ T cell levels. Loss of HIF-1α decreases the ratio of CD8+ to FOXP3+ cells in TILs. After antigenic restimulation, the generation of effector cytokines from HIF-1α mutant T cells was suppressed. Ectopic HIF-2α (but not HIF-1α) mediates the extensive changes in gene expression by altering the CD8+ T cell transcription factor network, regardless of VHL inhibition, including increased perforin, granzyme B, IL-2, integrins, and CXCR4. In addition, the increase in co-inhibitors such as lymphocyte activation gene-3 (LAG-3) and CTLA-4 and the decrease in IFN-γ expression is also mediated. Overall, these molecular expression changes enhance cytotoxic differentiation and lytic functions against cancer targets.

17However, the antitumor effects of CTLs under hypoxic conditions remain unclear. It has been reported that hypoxia impairs T cell function by reducing the levels of IFN-γ, IL-2, and NK group 2 member D (NKG2D)., This is more in line with the actual tumor, where CD8+ and CD4+ T cells are significantly reduced in hypoxic areas of the tumor. T cell proliferations were strongly correlated with oxygen concentrations and were significantly suppressed under hypoxia (pO2 = 1%), likely due to hypoxia-associated changes in Ca2+ homeostasis in T cells. HIF-1α inhibits IFN-γ, TNF-α, and granzyme B expressions in CD8+, CD4+ T, and NK cells, which induces resistance to PD-1/PD-L1 blockade and suppresses T cell toxicity. Hyperoxia treatment suppressed the expressions of adenosine, an immunosuppressive factor, and reactive nitrogen production, and increased IFN-γ levels and perforin granules. Sustained hypoxic stimulation induces mitochondrial stress, resulting in the loss of mitochondrial functions, elevated ROS levels in T cells, T cell failure, and impeded anti-PD-1 efficacy. Because of the Warburg effect in cancer cells, which “ferments” glucose into lactic acid, lactic acid is transported outside the cell to prevent excess lactic acid accumulation. This stabilizes the intracellular pH of cancer cells while acidifying the extracellular environment., HIF-1α induces high expression of tumor-associated carbonic anhydrase (CA), such as CA9 and CA12, which catalyze the reversible hydration of CO2 to carbonic acid. In hypoxic environments, the pH of the extracellular environment of cancer cells can be as low as 5.8–6.5, which inhibits CTL activation, proliferation, and cytokine production, and also triggers T cell apoptosis.

18Hypoxia induces cancer cells to express chemokines such as CC chemokine ligand 28 (CCL28) to recruit regulatory T cells (Tregs). HIF-1α promotes Treg polarization and significantly contributes to colorectal cancer development and progression. This mechanism had no significant effect on the inhibition of Foxp3 expressions. Inhibiting Treg HIF-1α expression suppressed cancer growth. However, the HIF-1α-dependent transcriptional program contributes to helper T cell (Th) 17 development by mediating glycolytic activities. Moreover, HIF-1α can activate RORvt and form a tertiary complex with retinoic acid-related orphan receptor γt (ROR-γt), as well as p300, and recruit it to the IL17 promoter. In addition, HIF-1α attenuates Treg development and differentiation by binding to Foxp3 and targeting it for proteasomal degradation.,, Tregs express immunosuppressive factors, immunosuppressive adenosine, and cytokines such as IL-10, IL-17, and IL-35 to inhibit effector T cell toxicity; therefore, they are closely associated with poor cancer prognosis. In addition, Tregs inhibit the expressions of nutrient transporters on CD8+ T cells, limiting nutrient uptake by T cells during activation, thereby suppressing T cell proliferation. Respiratory hyperoxia therapy may reduce the immunosuppressive effects of Tregs in the TME. Amphiregulin (Areg) is an epidermal growth factor receptor (EGFR) ligand, and Areg-EGFR promotes HIF-1α levels, leading to cancer progression. The lack of HIF-1α decreases the ratio of IFN-γ+ to FOXP3+ cells in CD4+ TILs, as HIF-1α deficiency reduces FOXP3 proteasomal degradation and cannot efficiently bind the IFN-γ promoter to drive Th1 responses.

Hypoxia and B cells

19The differentiation process of mammalian B cells includes pro-B, pre-B, immature B, and mature B cells. HIF-1α activity, which is regulated by miR-582, is high in human and murine bone marrow pro-B and pre-B cells, promoting cell proliferation, differentiation, apoptosis, and gene rearrangement. However, reduced immature B cell stages and sustained high activities of HIF-1α reduced the abundance of surface B cell receptors (BCR), CD19, and B cell activator receptors and increased the expression of the pro-apoptotic factor (BIM), preventing normal B cell development. Although hypoxia impairs B cell proliferation, it simultaneously alters B cell metabolism and promotes antigen-mediated differentiation. HIF transcription factors suppress the activities of prolyl hydroxydioxygenase, which stabilizes HIF by hydroxylating HIF-1α and HIF-2α in conjunction with pVHL to disrupt HIF. Therefore, reducing antigen-specific B cells in germinal centers (GCs; produce long-lived plasma cells and memory B cells) disrupts high-affinity IgG production and shifts to IgG2c, early memory B cells, and recall antibody responses. In contrast, sustained hypoxia or HIF induction induced by VHL deficiency inhibits mTOR complex 1 (mTORC1) activity in B lymphoblastoid cells, which impairs B cell clonal expansion, activation-induced cytosine deaminase (AID) expression, and the ability to produce IgG2c and high-affinity antibodies. HIF-1α is closely correlated with B-cell lymphoma (BCL-6). Upregulated BCL-6 promotes the immortalization of mouse embryonic fibroblasts and primary B cells by elevating cyclin D1 levels. HIF-1α binds CXC chemokine receptor type 4 (CXCR4) to promote B-cell viability. The immune effects of B cells on cancers have not been conclusively established. Large numbers of CD20+ B cell follicles and Foxp3+ low-infiltrating cells are associated with cancer survival and better recurrence-free survival outcomes in cancer patients, including gastric and pancreatic cancers., Activation of HIF in B cells modulates immune responses by inducing VEGF to increase lymphatic and endothelial vessel formation and enhance DC maturation and antigen presentation. Cancer-promoting effects of B cells have been reported. Hypoxia activates HIF-1α and induces autocrine transforming growth factor-beta (TGF-β) signaling, promoting myofibroblast activation, CXCL13 induction, B lymphocyte recruitment, and factor MYC secretion, which favors B cell proliferation and survival, and drives cancer recurrence. HIF-1α-dependent glycolysis facilitates CD1dhiCD5+ B cell expansion and promotes IL-10 expressions. B cell-derived IL-35 is associated with attenuated macrophage as well as inflammatory T cell viabilities and inhibited functions of B cells as antigen presenting cells (APCs). IL-10 and IL-35 promoted cancer cell metastasis, and inhibited anticancer immune responses in mice.– In addition, one of the mechanisms of origin of extracellular immunosuppressive adenosine relies on CD73+ and CD19+ extracellular vesicles (EVs) from B, which is regulated by HIF-1α., Regulatory B cells (Bregs) are a functional B cell subpopulation with the key function of secreting IL-10, thereby preventing the production of cytokines. HIF-1α is a tumor suppressor in some cancers. For instance, pancreatic-specific HIF-1α deficiency significantly accelerated Kras (G12D)-driven pancreatic adenoma formation with a significant increase in intrapancreatic B lymphocytes. Depletion of B cells increases exocrine tissue regeneration owing to a significant decrease in overall immune infiltrations and fibrosis. Pancreatitis-induced tissue hypoxia and HIF-1α accumulation-induced B-cell depletion enhances pancreatic regeneration. B cell depletion in mice with pancreatitis significantly enhanced tissue regeneration and chemotherapeutic drug resistance.

Hypoxia and macrophages

20Hypoxia, HIF-1α, and tumor secretion of multiple chemokines facilitate cancer-associated macrophage (TAM) recruitment to the TME.– TAMs constitute a plastic and heterogeneous cell population and can account for up to 50% of certain solid tumors. TAMs promote cancer progression by creating an immunosuppressive microenvironment, and enhancing the progression and metastasis of various cancers.– Hypoxia-induced HIF-1α promotes the adaptation of TAMs to the hypoxic environment and is associated with cancer prognosis. Lipopolysaccharides (LPS) promote HIF-1α expression by stimulating the expression of Toll-like receptors in macrophages. Hypoxia (1.5% oxygen) leads to inadequate T-cell responses by increasing macrophage pro-inflammatory responses, including TGF-β, increased platelet-derived growth factor (PDGF), phagocytosis maintenance, and reduced antigen presentation. Hypoxia enhances fibrosis by promoting pro-fibrotic cytokine responses and isolating fibroblasts in the vicinity of granulomas. The hypoxic environment leads to elevated HIF-1α levels in macrophages and promotes the expression of inducible nitric oxide synthase (iNOS), which rapidly blocks T cell proliferation through NO and subsequent peroxynitrite formation.– IL-15Rα+ TAMs downregulate CX3CL1 expression in cancer cells through the non-transcriptional activity of HIF-1α, reducing CD8+ T cells and/or increasing CD4+ T cells to reduce the ratio of CD8+ T cells to CD4+ T cells and thus weaken anti-cancer immunity. In addition, macrophages express HIF-2α under hypoxic conditions and inactivate drug-induced chemoresistance to 5-FU through HIF-2α-mediated specific overexpression of dihydropyrimidine dehydrogenase (DPD)., Furthermore, acidic TME affect TAMs. Lactate, converted from pyruvate in cancer cells, plays a key signaling role by inducing HIF-1α-mediated expression of vascular endothelial growth factor in other processes.– In addition, M2-like TAM promotes cancer progression by remodeling the extracellular microenvironment.

Hypoxia and NK cells

21NK cells are bone marrow-derived and account for 10–18% of peripheral blood mononuclear lymphocytes. NK cells can kill various cancer targets, including cancer cells with low expressions MHC-I. Some cancer cells secrete chemokines to recruit NK cells. For instance, HCC cells are often in hypoxic microenvironments, an environment that helps CD103+ DCs to take up and clear cancer DNA, which is enhanced by blocking cell surface protein (CD47). By secreting IL-12 and CXCL9, activated CD103+ DCs induce NK cell recruitment; upregulate the expression of granzyme B, NKG2D, IFN-γ and TNF-α; and downregulate the expression of NKG2A, which in turn enhances antitumor effects. However, under hypoxic conditions, most HCC cells highly express the CD47 protein, which is associated with poor prognostic outcomes., Expression of NKG2D receptors, intracellular perforin, and granzyme B in NK cells is severely impaired under hypoxic conditions, which suppresses NK cell immunotoxicity. Hypoxia promotes cancer cell metalloproteinase ADAM10 expression through HIF-1α, leading to shedding of NK cell activation ligand (MICA) from cancer cell surfaces, thereby attenuating NK cell-mediated lysis. In an inflammatory model, elevated NK cell HIF-1α levels stimulated the release of IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), enhancing antimicrobial defenses while promoting M1 macrophage polarization, leading to slow angiogenesis and wound healing. NK cell counts and cytotoxic effects were similarly suppressed in a chronic hypoxia mouse model, accompanied by inhibited IFN-γ secretion by NK cells. NK cells also secrete large amounts of MMP-9, which affects blood vessel remodeling. Although the absence of NK cell HIF-1α inhibits tumor growth, it is associated with various challenges. For example, deletion of HIF-1α in NK cells suppressed the expression of the angiostatic soluble form of VEGF receptor 1 (sVEGFR1) in cancer, increasing VEGF bioavailability in the TME and leading to non-productive angiogenesis. The immature vascular phenotype promotes cancer cell intravasation and distant pulmonary metastases from melanoma in vivo. Moreover, cancer cells influence the cytotoxic effects of NK cells. Upregulated HIF in the TME increases PD-L1 expression, decreases autophagic MHC-I expression, and inhibits NK cell recognition., HIF-2α promotes IL-10 release by activating the STAT3 signaling pathway in HCC cells, thereby inhibiting the killing activities of NK cells, which in turn promotes HCC recurrence and metastasis. HIF-2α stimulates ITPR1 expression in hypoxic cancer cells, activates autophagy in NK cells, inhibits granzyme B activity, and impairs the killing sensitivity of NK cells. Activated autophagy in hypoxic cancer cells selectively degrades the pro-apoptotic NK-derived serine protease GZMB/granzyme B, leading to the suppression of NK-mediated target cell apoptosis.

Hypoxia and neutrophils

22Neutrophils are the major players in the innate immune system. Neutrophil infiltration is uncommon in normal tissues. Neutrophils are glycolytic cells that derive little ATP from oxidative phosphorylation and require gluconeogenesis to generate intracellular glycogen stores to kill bacteria. In a hypoxic environment, neutrophils reduce glycogen recycling, leading to impaired functions, and consume extracellular proteins to promote their own central carbon metabolism to maintain their functions. Infiltrating neutrophils in the TME, known as tumor-associated neutrophils (TANs), promote cancer growth and is strongly associated with poor prognosis. For instance, neutrophil-derived ROS damages hepatocyte DNA to drive HCC development. Neutrophils can eliminate bacteria from the body, forming an immune barrier that allows cancers to start growing back;, therefore, they are closely correlated with prognostic outcomes of cancer patients., Elimination of neutrophil infiltration leads to cancer regression and prolonged survival outcomes. Sequencing of pancreatic single-cell transcriptome revealed that BHLHE40 is a key regulator of neutrophil polarization toward the TAN-1 phenotype, which has pro-cancer and immunosuppressive functions. However, the associated mechanism should be investigated. Neutrophils have an extensive mitochondrial network that uses the glycolytic product (glycerol-3-phosphate) to maintain polarized mitochondria and produce ROS to regulate HIF-1α stability. Neutrophil extracellular traps (NETs) promote cancer cell colonization by enhancing migration, invasion and cancer cell stemness, leading to poor cancer prognosis. Interestingly, NET formation is strongly associated with elevated HIF-1α levels in neutrophils. Downregulation of neutrophil HIF-1α can effectively inhibit NET-mediated circulating tumor cell (CTC) metastasis and prolong the median survival of mice with breast cancer lung metastasis. However, some experiments have shown the anticancer effects of NK cells. Hypoxia favors neutrophil viability and function. Hypoxia recruits polymorphonuclear neutrophils (PMNs), which are the main effector cells against endometrial adenocarcinoma growth, and induces cancer cell detachment from the basement membrane. Upon relief of tumor hypoxia, recruitment of PMNs to the TME is significantly reduced; however, the recruited cells can efficiently kill cancer cells by releasing NADPH oxidase-associated MMP-9 and ROS.

Hypoxia and MDSCs

23Myeloid-derived suppressor cells (MDSCs) can suppress immune cell activity. Hypoxia and HIF-1α drive MDSCs recruitment to the TME., This is because cancer cells in hypoxic areas express various cytokines, such as chemokine (C-C motif) ligand 26, G-CSF, and IL-6, to recruit MDSCs.,, Functionally, MDSCs enhance the evasion of cancer cells from immune surveillance and promote cancer drug resistance. Inhibiting the infiltration of MDSCs improves anti-tumor effects. In an HCC model, Chiu et al. found that hypoxia-induced HIF-1α promotes the expression of ENTPD2/CD39L1, an indicator of poor HCC prognosis, which is thought to convert extracellular ATP to 5’-AMP, preventing the differentiation of MDSCs, but maintaining their survival. In addition, under hypoxic conditions, MDSCs express multiple immunosuppressive factors. For instance, PD-L1 is secreted by hypoxia-induced HIF-1α, but not HIF-2α in MDSCs, arginase and NO are promoted by HIF-1α-induced miR-210 expression,, surface ectonucleotidases CD39 and CD73, TGF-β1, and exosomes, such as S100A9, RAR-related orphan receptor alpha (RORA), and PTEN,,, promote cancer cell stemness and growth and inhibit CTL function. Hypoxia through HIF-1α dramatically alters the function of MDSCs in the TME and redirects their differentiation toward TAMs, although the macrophage subtype has not been clearly established. These effects may be attributed to the ability of MDSCs to express SIRT1, a factor that regulates the glycolytic activities of MDSCs and affects the functional differentiation of MDSCs, and some miR-29a-containing exosomes.

Hypoxia and ILCs

24Innate lymphocytes (ILCs) consist of NK cells ILC1, ILC2, and ILC3, and are involved in the immune response to virus, bacteria, parasites, and transformed cells., Their roles in cancer immunity and immunotherapy have not been established., Specific changes in cancer cytokines alter ILC composition in cancers by inducing plasticity and altering ILC functions., IL-15 promoted ILC1 granzyme A expressions and cytotoxicity, induced the apoptosis of murine leukemia stem cells (LSC), maintained anticancer immunity, and was positively correlated with survival outcomes.– IL33-activated ILC2 selectively expresses chemokine ligand 5 (CCL5), which recruits CD103+ DCs into the TME and activates CD8+ T cells to lyse cancer cells. IL-33 results in massive amplifications of ILC2 and produces CXCR2 ligands from these cells, which enhances cancer cell-specific apoptosis through CXCR2. Administration of hypoxic ILC2 resulted in a higher cancer volume, suggesting that hypoxia-exposed ILC2 enhanced the progression of pancreatic cancer cells. These outcomes were attributed to the conversion of ILC2 to ILCregs under hypoxic conditions, which inhibited T cell infiltration and IFN-γ expression by secreting IL-10. IL-25 promotes intra-tumoral ILC2 infiltration and enhancing the ability of cancer-infiltrating MDSCs to suppress antitumor immunity and reduce survival outcomes in colorectal cancer (CRC) patients. ILC3 have antitumor effects. Their intrinsic disruption in CRC drives dysfunctional adaptive immunity, cancer progression, and immunotherapeutic resistance. The production of chemokines (CCL20) and pro-inflammatory cytokines (IL-1β) at the tumor site leads to ILC3 recruitment and activation. ILC3 secrete the chemokine CXCL10, which recruits CD4+ and CD8+ T cells and promotes antitumor immune responses. IL-22, secreted by ILC3 cells, is required for initiation of DNA damage responses (DDR) after DNA damage. Stem cells that lose IL-22 signaling and are exposed to carcinogens escape DDR-controlled apoptosis, develop more mutations, and are more likely to cause colon cancer. The interaction between immune cells and TME is showed in Fig. 6.

Hypoxia and chemotherapeutic resistance

25In vivo experiments have shown that hypoxia increases the tolerance of cancer cells to drug toxicity.– Hypoxia induces high expression of drug resistance genes in cancer cells, increases chemotherapeutic drug efflux, and reduces intracellular drug concentrations. Once they are combined with anticancer drugs, P-glycoprotein (PGP), known as multidrug resistance protein 1 (MDR1), and breast cancer resistance protein (BCRP) are ATP-binding cassette (ABC) transporters and energy-dependent drug excretion pumps that can pump drugs out of the cell by providing energy through ATP. Therefore, the intracellular concentration of drugs continues to decrease, which weakens their cytotoxic effects until they are dissipated, and drug resistance occurs. ROS generated under hypoxic conditions induce PGP and BCRP expression through HIF-1α and increase cancer cell drug resistance. HIF-1α induces multidrug resistance-associated protein 1 (MRP1) expressions and enhances drug resistance in colon cancer cells. Moreover, HIF-1α enhances the inactivation of chemotherapeutic drugs and reduces their cytotoxic effects. Cytidine deaminase (CDD), an important metabolic enzyme involved in drug resistance development in cancer cells, is derived from cancer cells or bacteria within cancer cells. Elevated CDD levels promote the metabolism of gemcitabine to its inactive form. Moreover, solute carrier (SLC) transport proteins are primarily involved in the uptake of small molecules into cells, and their absence affects the uptake of chemotherapeutic agents into cancer cells, leading to drug resistance. The role of hypoxia in relation to CDD and SLC has not been fully established. Recently, alternative resistance pathways have been identified in hypoxic cancer cells. For instance, cancer and stromal cells in the TME, such as cancer-associated fibroblasts, secrete various cytokines, including IL-6, which induces HIF-1α expressions to regulate downstream chemotherapeutic resistance genes, such as olfactomedin 4 (OLFM4), pyruvate kinase muscle 1 (PKM1) that enhances mitochondrial oxidative phosphorylation (OXPHOS), and expressions of non-coding genes, for example, miR-27a that increases PGP expression, to promote chemoresistance acquisition in cancer cells.– HIF-1α and cancer-associated fibroblast-secreted TGF-β signaling synergistically promote GLI family zinc finger 2 (GLI2) expressions through SMAD3, inducing CRC cell stemness and chemoresistance. Upregulated HIF-2α promotes sorafenib resistance in hypoxic HCC cells by activating the TGF-α/EGFR and COX-2 pathways., Under normoxic conditions, autophagy activation did not counteract cisplatin-induced stress, leading to cell death, whereas under hypoxic conditions, autophagy induction was enhanced, resolving cisplatin-induced stress and inhibiting the cisplatin-induced BCL2 interacting protein 3 (BNIP3) death pathway, allowing cell survival. Downregulation of BNIP3 may contribute to the resistance of pancreatic cancer to hypoxia-induced cell death. However, in non-small lung cancer samples, high expression of BNIP3 was significantly associated with HIF-1α and poorer overall survival was associated. Due to fibrosis and formation of non-functional vessels in the TME, drug diffusion and delivery to cells away from functional vessels is decreased, and this may trigger drug resistance in cancer cells. In addition, an altered pH gradient in the TME can attenuate drug action in cells (for example, alkylating agents and antimetabolites) to enhance drug resistance. The mechanisms of hypoxia-enhanced tumor chemotherapy resistance is showed in Fig. 7.

Hypoxia and radiation resistance

26Radiotherapy directly destroys macromolecule fixation and leads to DNA damage through the generation of free radicals, such as hydroxyl (OH•) and hydrogen (H•) radicals, by ionizing radiation (IR), a process known as “oxygen fixation theory”. The damage caused by radiotherapy is permanent and irreversible. Hypoxia reduces the effectiveness of radiotherapy and free radicals become unstable, leading to limited extent of their damage, and most of the damage can be easily repaired., Classical in vitro and in vivo experiments have shown that at O2 (pO2) partial pressures below 10 mmHg, tumor cells can acquire radiobiologic hypoxia and thus become relatively resistant to radiotherapy. For instance, at 1 mm Hg, cancer cells are three times more resistant to radiation than ordinary oxygen cells. Several preclinical and clinical trials have demonstrated that the number of lethal DNA DSB formed under hypoxic conditions is also reduced by 2 to 3-fold and hypoxia can alter the expression and function of DNA DSB-associated genes. Under hypoxic conditions, additional DNA repair pathways can be activated.,– HIF-1α stimulates DNA-dependent protein kinase (DNA-PK) expression and repairs DNA DSB caused by ionizing radiation. Radiation upregulates HIF-1 expression and enhances its activity in cancer cells. Elevated HIF-1α levels confer radioresistance via various pro-cancer mechanisms. HIF-1α promotes ATP metabolism, and p53 activation and stimulates EC survival, thereby mediating the ultimate cancer radiation responses., The serine peptidase inhibitor Kazal type 1 (SPINK1) is secreted in a HIF-dependent paracrine manner to reduce radiation-induced DNA damage and enhance radiation resistance in adjacent cancer cells through EGFR and nuclear factor erythroid 2-related factor 2 (NRF2). Radiation-induced EC death leads to secondary tumor cell killing. The vascular system also affects radiation therapy. Radiation-induced secretion of VEGF, FGF, and PDGF by cancers protects the cancer vasculature from radiation-mediated cytotoxicity and enhances the radioresistance of ECs.– Thus, VEGF, FGF, and PDGF inhibitors can significantly improve the efficiency of radiotherapy., The radiosensitivity of hypoxic cancer cells was showed to be significantly increased after reoxygenation. Elevated H2O2 levels in cancer tissues exacerbate hypoxia-induced resistance to radiotherapy. Reducing oncological cellular H2O2 or using it to generate oxygen through chemical reactions may improve radiotherapeutic outcomes. However, these mechanisms require further evaluation (Fig. 8).

Targeted therapy

27Approximately 80–90% of deaths among cancer patients are directly or indirectly attributed to drug resistance. Progress in the development of new drugs is also hampered by drug resistance, which has become a considerable challenge in cancer treatment. Hypoxia drives cancer development and progression. Therefore, it is essential to increase the oxygen concentration in TME. Oxygen delivery in the TME is increased by enhancing cancer vascular formation to elevate oxygen levels, however, the vessels formed in cancers are usually abnormal and non-functional. Intravenous oxygen delivery to the cancer through blood is not feasible for reasons such as the potential risk of systemic ROS exposure and the low solubility of oxygen in blood. Increasing oxygen delivery by increasing blood flow to the tumor through pharmacological vasodilatation methods has been proposed, but in practice it is difficult to improve or reduce blood flow to the tumor tissue. To overcome this challenge, nano- and bio-based technologies have been used to carry oxygen generators to generate enough oxygen in the target cancer such as pancreatic ductal adenocarcinoma, colorectal cancer, fibrosarcoma, melanoma, etc., which aids in drug delivery and significantly improves the effectiveness of chemotherapy, radiotherapy as well as immunotherapy.,– Moreover, the reoxygenation process generates large amounts of ROS, which results in DNA damage, contributing to cancer cell death., However, the damage this brings to the surrounding normal cells is a matter of concern. Second, inhibition of hypoxia-induced HIF and its downstream target genes is an effective strategy. For instance, 32–134D, a low-molecular-weight compound that inhibits HIF-1/2-mediated gene expression in HCC cells, combined with anti-PD-1 increased HCC eradication rates in mice (from 25 to 67%). HIF-1α inhibitors, such as topotecan, bortezomib (PS-341) as well as HIF-2α inhibitors, such as PT2399, PT2385 and PT2977, inhibit HIF-1/2α activities and their downstream target gene expressions., These inhibitors reduce VEGF levels in circulating tumor cells (such as neuroblastoma, multiple myeloma, HCC and renal cell carcinoma) to inhibit tumor angiogenesis,– and enhances the effects of chemotherapeutic drugs, such as oxaliplatin, to inhibit colorectal cancer cell proliferation. Hypoxia in the TME provides a special environment for the effects of some drugs, called hypoxia-activated prodrugs (HAPs). For instance, evofosfamide (TH-302) and tarloxotinib-effector inhibited cancer growth by suppressing signaling and cell proliferation in patient-derived cancer cells in vitro and in mouse xenograft models., However, there is controversy in the clinical treatment of advanced soft tissue sarcoma., Mechanistically, DNA dioxygenase ten-eleven translocation (TET)2 is recruited by the transcription factor (HNF4α) to activate FBP1 expressions, thereby antagonizing the functions of HIF-1/2α) in metabolic reprogramming to suppress clear cell renal cell carcinoma growth. Clinical trials regarding hypoxia-targeted therapy are summarized in Table 2.

28These clinical trials were designed using hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting HIF and downstream targets. Hypoxia tracers can visualize and quantify tumor hypoxia, assisting clinicians in the non-invasive detection and assessment of tumor hypoxia levels, and with the aid of PET imaging can be used to monitor the dynamic response of patients to treatment, potentially allowing for individualized patient treatment., Hypoxia-activated prodrugs can selectively target hypoxic tumor cells, have hypoxia-selective cytotoxicity, and exhibit broad antitumor activity.,, HIF and downstream gene-targeted drugs effectively inhibited tumor even, significantly improved patient survival, and phenocopied better tolerability.– However, these drugs have certain toxic side effects, and common adverse events include headache, fatigue, nausea, vomiting, diarrhea and dehydration, and serious adverse events include Gastrointestinal bleeding, blood clots/deep vein thrombosis, lymphocytopenia, febrile neutropenia, anemia and triggering secondary infections. Some clinical trials do not have sufficient data to analyze the safety and efficacy of drugs.

Hypoxia and immunotherapy

29Hypoxia inhibits anti-cancer immune sensitivity. Reduction of the hypoxic environment in the TME increases the efficacy of immune checkpoint blockade (ICB) against cancers in vivo. The rational use of the pulsatile system of the TME can ameliorate hypoxia. Increasing the oxygen partial pressure through intravenous oxygenation can reverse hypoxia in the TME. However, some of the vessels in cancer are abnormal and non-functional. Therefore, vascular remodeling in the TME is necessary to ameliorate hypoxia. Elevated levels of Delta-like 1 (DLL1) in breast and lung cancer induce long-term cancer vascular normalization to alleviate cancer hypoxia, promote the accumulation of IFN-γ-expressing CD8+ T cells, and enhance macrophage polarization toward the M1-phenotype. Hyperoxia upregulates MHC-I expression in cancer cells, enhances T cell-mediated cytotoxicity, promotes the anti-cancer activities of NK cells, reduces the immunosuppressive effects of Tregs in the TME, and inhibits the production of MDSC-derived exosomes to reduce cancer cell stemness., Pro-oxidants can also be used to increase oxygen levels in the TME. Wu et al. developed nanoparticle-stabilized oxygen microcapsules that could be precisely targeted to pancreatic ductal adenocarcinoma (PDAC), improving hypoxia and significantly increasing the efficacy of anti-PD-1 antibodies against PDAC. Treatment with oxygen microcapsules combined with anti-PD-1 antibodies alleviates TAM infiltration, polarizes macrophages from the pro-cancer M2 phenotype to the anti-cancer M1 phenotype, and increases the proportion of TME Th1 cells and CTLs to enhance anti-cancer immune effects. The oxygenating agent (TH-302) eliminates hypoxia in cancers and promotes T-cell infiltration. The pro-oxidant adaptor (p66SHC) reduces ATP production in B cells by limiting glycolysis and compromising mitochondrial integrity, while activating AMPK to promote B cell mitochondrial autophagy and limiting plasma cell differentiation. Suppression of HIF pathway-mediated PD-L1 is an important measure for enhancing cancer immune responses. Inhibition of HIF-1α synthesis suppresses PD-L1 expression and induces lysosomal degradation of PD-L1, enhancing the ability of CTLs to kill cancer cells. The deletion of HIF-1α in NK cells significantly inhibits cancer growth and improves patient survival outcomes by activating the NF-κB pathway and stimulating the expression of effector molecules, such as IL-18. Single inhibition of HIF-1α in immune cells restores immune cytotoxicity; however, it also induces PD-L1 expression in cancer cells, impairing anticancer immunity. Therefore, multichannel combination therapy is vital for cancer treatment. Hypoxia leads to the increased expression of immune checkpoints and promotes fibrosis, thereby suppressing the efficacy of cancer immunotherapy. Increasing the oxygen concentration affects cancer immune responses by altering the extracellular matrix. For instance, hyperbaric oxygen (HBO) promotes PD-1 antibody delivery and T cell infiltration into the cancer parenchyma by depleting major components of the extracellular matrix, such as collagen and fibronectin. Genetic engineering approaches can be used to construct high-affinity NK (haNK) cells, which can express high-affinity CD16 receptors and IL-2, improve tolerance against acute hypoxia, and maintain the functions of NK cells to kill cancer cells.

Hypoxia and radiotherapy

30Radiotherapy is a non-invasive oncologic treatment approach for drug-resistant cancers. It is based on the principle of targeting cancer tissues with X-rays or gamma rays, which directly or indirectly damage biomolecules to ionize the surrounding water and generate ROS, inducing DNA damage and apoptosis., Oxygen in the TME can anchor broken ends of DNA and form stable organic peroxide groups that inhibit further DNA repair. However, local hypoxia in the TME markedly reduces the therapeutic efficacy of radiation therapy. In addition, radiotherapy requires high doses of X-rays to treat cancers, which can cause serious side effects. By utilizing the sustainable production of O2 from endogenous H2O2 decomposition, cancer hypoxia can be improved and the efficacy of radiotherapy is enhanced. Chai et al. found that under continuous external irradiation with a 660 nm laser and X-ray beams, cyanobacteria continuously photosynthesized and released oxygen, and the large amount of ROS produced by the two-dimensional (2D) bismuth radiosensitizer greatly enhanced the efficacy of radiation therapy and inhibited cancer growth in vivo. Improving hypoxia increases the sensitivity of cancer cells to radiotherapy, which may be related to HIF-1α inhibition in cancer cells by changing the optical redox status. The mechanisms involved in hypoxia-induced tolerance to radiotherapy in cancer cells should be investigated further.

Nano application therapy

31Nanoparticles are characterized by small sizes, large surface areas, high bioavailability, and good biocompatibility, and have great potential for safely and efficiently transporting external oxygen to the hypoxic TME. The nanocomposite “oxygen bomb” PSPP-Au980-D is used to precisely locate the hypoxic microenvironment of pancreatic cancer, and through different nm laser irradiation, it can improve hypoxia, generate singlet oxygen, and enhance the efficacy of photodynamic therapy (PDT). The use of an acidic microenvironment to generate oxygen is a feasible method. For instance, an acidic environment triggers a reaction between MnO2 and H2O2, releasing large amounts of oxygen to alleviate intra-tumoral hypoxia. Fragmented human-induced pluripotent stem cells (iPSCs) release cancer-sharing antigens, which trigger strong innate and adaptive immune responses against cancers, promote dendritic cell maturation, and activate effector T and NK cells. Meanwhile, they also decreased the amount of Treg cells. iPS-MnO2@Ce6 significantly inhibited cancer growth, metastasis and reduced mortality in cancer-bearing mice models. Nanoparticles can also host various drugs, such as oxygenating agents, chemotherapeutic agents and immune-boosting drugs, improving the anti-cancer effects. Manganese dioxide based nanocarriers can enhance the anticancer effects of piggyback paclitaxel by alleviating the degree of hypoxia in the in situ glioma microenvironment. Porous Au@Pt core-shell nanostructures inhibit the expressions of HIF-1α and MDR1 gene by oxidizing the TME, thereby reducing the extracellular secretion of adriamycin (DOX) and enhancing the efficacy of chemo-photothermal therapy. When hybrid nanospheres containing Fe3+, aggregation-induced emission (AIE) photosensitizer, and Bcl-2 inhibitor of sabutoclax were consumed by cancer cells, they increased intratumoral oxygen concentration through Fe3+-mediated Fenton reactions, and intracellular PDT resistance of the AIE photosensitizer was mitigated by sabutoclax. Remodeling the tumor immune microenvironment by nanoparticle technology can achieve efficient cancer therapy. Mesoporous silica nanoparticles (MSNs) in combination with pro-oxidants and mitochondrial respiration inhibitors can alleviate the hypoxic environment and inhibit MDSCs infiltration. TK-M@Man-HMPB/HCQ alleviated hypoxic microenvironment-induced TAM polarization, promoted CTL infiltration, and significantly inhibited cancer growth. Novel poly (vinylpyrrolidone) (PVP)-modified BiFeO3/Bi2 WO6 (BFO/BWO) with a p-n type heterojunction reshapes the immunosuppressive TME. It triggers H2O2 catabolism to generate O2 to alleviate cancer hypoxia, enhance PDT and radiotherapy sensitivity, promote TAM polarization from the M2 to the M1 phenotype, and inhibit HIF-1α expression. This photo-activated nanoconjugated radiotherapy can activate and recruit T cells and stimulate TAMs toward the M1 phenotype, significantly reversing the immunosuppressive TME to immunoreactive TME and further enhancing the immune memory response. Advances in nanotechnology to improve the hypoxic TME, or to combine chemotherapy, radiotherapy, and immunotherapy, have achieved satisfactory outcomes, compared to traditional treatments, and may become a treatment measure with great potential in the future.

Biotherapy

32Accumulating evidence suggests that microbiota play an important role in cancer by damaging cellular DNA, inducing transformation, activating and altering stromal cell components in the TME, and influencing cellular metabolism., The microbiota characteristics under hypoxic conditions are currently not fully understood. Recent research has demonstrated that a combination of live bacteria and treatment modalities such as surgery, chemotherapy, and radiotherapy can produce good clinical outcomes. Certain bacteria have the potential to gravitate to the hypoxic core of cancer cells and can spread and proliferate. Spores of the anaerobic bacterium Clostridium novyi-NT were used to treat the transplanted tumors in mice. In several mouse models including colorectal cancer, biliary cancer, melanoma and squamous cell carcinoma, this bacterium was found to significantly improve the efficacy of radiotherapy. The use of the attenuated pathogenic anaerobe Salmonella VNP20009 to target the cancer hypoxic region, equipped with photosensitizers and bromodomain and extra terminal domain (BET) protein inhibitors with mitochondrial targeting properties improved the heat elimination abilities of photothermal therapy (PTT) and significantly inhibited the expressions of PD-L1 in cancer cells, thereby enhancing and maintaining a durable immune response. Bioluminescent bacteria designed by transforming attenuated Salmonella typhimurium strains effectively increased PDT and promoted inflammation by converting macrophages M2 to M1, activated NK cells, CD4+ Th cells and CD8+ T cells in the TME, reduced intratumoral immunosuppressive Tregs, and upregulated the expressions of various effector cytokines. Salmonella preferentially localizes sites and proliferates in hypoxic cancers, due to this advantage, Salmonella is also used as a cancer targeting vector to deliver different therapeutic agents and to achieve synergistic anticancer effects. However, colonized Salmonella recruits a large number of neutrophils, thus favoring cancer growth., The elimination of Salmonella-recruited neutrophils facilitates complete cancer eradication and reduces side effects. Delivery of peroxidase is an effective strategy for reducing resistance to radiotherapy. The peroxidase membrane vesicles (EMs) of Escherichia coli have higher peroxidase activity than free peroxidase, which decomposes H2O2 into oxygen to alleviate cancer hypoxia. Combined with their immunostimulatory properties, EMs can effectively enhance the effects of radiation therapy and induce anticancer immune memory. Maximizing the use of live bacteria under hypoxic conditions has the potential to be a therapeutic modality for the treatment of cancer.

Conclusions and perspectives

33Over the last 60 years, extensive progress has been made in the understanding of hypoxia-mediated signaling pathways. Hypoxia-based research has provided new insights into how hypoxia works and has laid the foundation for the development of targeted therapies that can improve patient prognosis. Carcinogenic factors and mature cancer characteristics promote hypoxia in the TME, and cancer cells adapt to hypoxia by changing their own metabolism through key genes such as HIFs. With advances in analytical tools and genomic technologies, such as pan-genomic analysis, are important for in-depth studies of HIFs., Hypoxia-induced pathways can alter the malignant behavior of cancer cells. Under hypoxic conditions, most downstream targets are HIF-dependent. Whether there are other key genes independent of HIFs requires further investigation. For instance, hypoxia-induced RNA editing by endogenous RNA editing enzyme can be mimicked by inhibiting mitochondrial respiration and occurs independently of HIF-1α to facilitate adaptation to hypoxic stress. Moreover, hypoxia reshapes the stromal cell properties of the TME, especially with the rise of immunotherapy, and both innate and adaptive immune cells in hypoxic environments have received extensive attention. However, despite significant breakthroughs, some results remain controversial. The reasons for this may be related to tissue specificity in addition to the experimental tools used and design bias, and mature modeling is also critical. The composition of the TME is diverse, and in addition to its own components, other foreign components may be present, such as microbiota, an emerging field that plays an important role in various cancers. Microbiota in the TME is one of the factors that form and maintain chronic hypoxia, activates HIF-1α in a non-hypoxic manner, increases HIF-1α mRNA levels, stabilizes HIF-1α protein, and induces the expression of HIF-1α regulatory genes.,, Changes in the characteristics of the microbiota in hypoxic environments and their effects on tumors are interesting and deserve further exploration. Therapeutic measures based on these characteristics, including targeted therapy, immunotherapy, chemotherapy, radiotherapy, radiotherapy, and biotherapy, offer good prospects. However, the complexity of the tumor relationship makes it inefficient to treat cancer from a single perspective. Multidisciplinary combination therapy, such as biology, chemistry, materials, machinery, electronics, artificial intelligence, and other multidisciplinary approaches for cancer (especially refractory cancer), is an interesting trend. Extensive study is still required before the development and implementation of efficacious and robust hypoxia-related precision treatment.

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Höckel M, Schlenger K, Höckel S, Vaupel P. Hypoxic cervical cancers with low apoptotic index are highly aggressive. Cancer Res. 1999;59:4525-4528.
Not in our library
115.
Shyu K-G, et al. Hypoxia-inducible factor 1alpha regulates lung adenocarcinoma cell invasion. Exp. Cell Res. 2007;313:1181-1191.
Not in our library10.1016/j.yexcr.2007.01.013
116.
Dong L, et al. Arylsulfonamide 64B inhibits Hypoxia/HIF-induced expression of c-Met and CXCR4 and reduces primary tumor growth and metastasis of uveal melanoma. Clin. Cancer Res. 2019;25:2206-2218.
Not in our library10.1158/1078-0432.ccr-18-1368
117.
Zhu Y, et al. C-C chemokine receptor type 1 mediates osteopontin-promoted metastasis in hepatocellular carcinoma. Cancer Sci. 2018;109:710-723.
Not in our library10.1111/cas.13487
118.
Colla S, et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesis. Blood. 2007;110:4464-4475.
Not in our library10.1182/blood-2007-02-074617
119.
Pez F, et al. The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. Cancer Res. 2011;71:1647-1657.
Not in our library10.1158/0008-5472.can-10-1516
120.
Wei H, et al. Long non-coding RNA PAARH promotes hepatocellular carcinoma progression and angiogenesis via upregulating HOTTIP and activating HIF-1α/VEGF signaling. Cell Death Dis. 2022;13:102.
Not in our library10.1038/s41419-022-04505-5
121.
Rofstad EK. Microenvironment-induced cancer metastasis. Int J. Radiat. Biol. 2000;76:589-605.
Not in our library10.1080/095530000138259
122.
Chan DA, Giaccia AJ. Hypoxia, gene expression, and metastasis. Cancer Metastasis Rev. 2007;26:333-339.
Not in our library10.1007/s10555-007-9063-1
123.
Shi Q, et al. Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin. Cancer Res. 1999;5:3711-3721.
Not in our library
124.
Graeber TG, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379:88-91.
Not in our library10.1038/379088a0
125.
Zhang L, Hill RP. Hypoxia enhances metastatic efficiency by up-regulating Mdm2 in KHT cells and increasing resistance to apoptosis. Cancer Res. 2004;64:4180-4189.
Not in our library10.1158/0008-5472.can-03-3038
126.
Hypoxia in human soft tissue sarcomas: Adverse impact on survival and no association with p53 mutations · 2001
No notice
127.
Löfstedt T, et al. HIF-1alpha induces MXI1 by alternate promoter usage in human neuroblastoma cells. Exp. Cell Res. 2009;315:1924-1936.
Not in our library10.1016/j.yexcr.2009.02.015
128.
Li F, et al. Myc stimulates nuclearly encoded mitochondrial genes and mitochondrial biogenesis. Mol. Cell Biol. 2005;25:6225-6234.
Not in our library10.1128/mcb.25.14.6225-6234.2005
129.
Zhang H, et al. HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity. Cancer Cell. 2007;11:407-420.
Not in our library10.1016/j.ccr.2007.04.001
130.
Nilsson JA, Cleveland JL. Myc pathways provoking cell suicide and cancer. Oncogene. 2003;22:9007-9021.
Not in our library10.1038/sj.onc.1207261
131.
HIF-1α and HIF-2α differently regulate tumour development and inflammation of clear cell renal cell carcinoma in mice · 2020
No notice
132.
Das B, et al. Regulates the stemness pathway via and to maintain self-renewal in cancer stem cells versus non-stem cancer cells. Cancer Res. 2019;79:4015-4025.
Not in our library10.1158/0008-5472.can-18-2847
133.
Pouysségur J, et al. ‘Warburg effect’ controls tumor growth, bacterial, viral infections and immunity - Genetic deconstruction and therapeutic perspectives. Semin Cancer Biol. 2022;86:334-346.
Not in our library10.1016/j.semcancer.2022.07.004
134.
Liu X, et al. Hypoxia-induced upregulation of Orai1 drives colon cancer invasiveness and angiogenesis. Eur. J. Pharm. 2018;832:1-10.
Not in our library10.1016/j.ejphar.2018.05.008
135.
Liu M, et al. Hypoxia-inducible factor 1-alpha up-regulates the expression of phospholipase D2 in colon cancer cells under hypoxic conditions. Med. Oncol. 2015;32:394.
Not in our library10.1007/s12032-014-0394-9
136.
Du K, et al. ANXA3 is upregulated by hypoxia-inducible factor 1-alpha and promotes colon cancer growth. Transl. Cancer Res. 2020;9:7440-7449.
Not in our library10.21037/tcr-20-994
137.
Ding X, et al. CTHRC1 promotes gastric cancer metastasis via HIF-1α/CXCR4 signaling pathway. Biomed. Pharmacother. 2020;123:109742.
Not in our library10.1016/j.biopha.2019.109742
138.
Hypoxia promotes breast cancer cell invasion through HIF-1α-mediated up-regulation of the invadopodial actin bundling protein CSRP2 · 2018
Not checked
139.
Khumukcham SS, et al. A reciprocal feedback loop between HIF-1α and HPIP controls phenotypic plasticity in breast cancer cells. Cancer Lett. 2022;526:12-28.
Not in our library10.1016/j.canlet.2021.11.002
140.
Yang J, et al. HIF-2α promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J. Exp. Clin. Cancer Res. 2016;35:26.
Not in our library10.1186/s13046-016-0298-y
141.
Wang C, Han C, Zhang Y, Liu F. LncRNA PVT1 regulate expression of HIF1α via functioning as ceRNA for miR‑199a‑5p in non‑small cell lung cancer under hypoxia. Mol. Med. Rep. 2018;17:1105-1110.
Not in our library10.3892/mmr.2017.7962
142.
Liu L, et al. Hypoxia promotes gastric cancer malignancy partly through the HIF-1α dependent transcriptional activation of the long non-coding RNA GAPLINC. Front Physiol. 2016;7:420.
Not in our library10.3389/fphys.2016.00420
143.
Zeng Z, et al. LncRNA-MTA2TR functions as a promoter in pancreatic cancer via driving deacetylation-dependent accumulation of HIF-1α. Theranostics. 2019;9:5298-5314.
Not in our library10.7150/thno.34559
144.
Fibroblast growth factor 11 (FGF11) promotes non-small cell lung cancer (NSCLC) progression by regulating hypoxia signaling pathway · 2021
Not checked
145.
Xia X, et al. Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop. Oncogene. 2020;39:6231-6244.
Not in our library10.1038/s41388-020-01425-6
146.
Zhang K-D, et al. MiR-301a transcriptionally activated by HIF-2α promotes hypoxia-induced epithelial-mesenchymal transition by targeting TP63 in pancreatic cancer. World J. Gastroenterol. 2020;26:2349-2373.
Not in our library10.3748/wjg.v26.i19.2349
147.
Sun S, et al. Hypoxia-responsive miR-141-3p is involved in the progression of breast cancer via mediating the HMGB1/HIF-1α signaling pathway. J. Gene Med. 2020;22:e3230.
Not in our library10.1002/jgm.3230
148.
Warburg O. On the origin of cancer cells. Science. 1956;123:309-314.
Not in our library10.1126/science.123.3191.309
149.
Shrieve DC, Deen DF, Harris JW. Effects of extreme hypoxia on the growth and viability of EMT6/SF mouse tumor cells in vitro. Cancer Res. 1983;43:3521-3527.
Not in our library
150.
Gordan JD, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell. 2008;14:435-446.
Not in our library10.1016/j.ccr.2008.10.016
151.
Firth JD, Ebert BL, Pugh CW, Ratcliffe PJ. Oxygen-regulated control elements in the phosphoglycerate kinase 1 and lactate dehydrogenase A genes: similarities with the erythropoietin 3’ enhancer. Proc. Natl Acad. Sci. USA. 1994;91:6496-6500.
Not in our library10.1073/pnas.91.14.6496
152.
Semenza GL, Roth PH, Fang HM, Wang GL. Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia-inducible factor 1. J. Biol. Chem. 1994;269:23757-23763.
Not in our library10.1016/s0021-9258(17)31580-6
153.
Discher DJ, et al. Hypoxia regulates beta-enolase and pyruvate kinase-M promoters by modulating Sp1/Sp3 binding to a conserved GC element. J. Biol. Chem. 1998;273:26087-26093.
Not in our library10.1074/jbc.273.40.26087
154.
Liu X, et al. Chromatin remodeling induced by ARID1A loss in lung cancer promotes glycolysis and confers JQ1 vulnerability. Cancer Res. 2022;82:791-804.
Not in our library10.1158/0008-5472.can-21-0763
155.
Koslowski M, et al. Multiple splice variants of lactate dehydrogenase C selectively expressed in human cancer. Cancer Res. 2002;62:6750-6755.
Not in our library
156.
Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis · 2003
No notice
157.
Osthus RC, et al. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J. Biol. Chem. 2000;275:21797-21800.
Not in our library10.1074/jbc.c000023200
158.
Kim J-w, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177-185.
Not in our library10.1016/j.cmet.2006.02.002
159.
Dupuy F, et al. PDK1-dependent metabolic reprogramming dictates metastatic potential in breast cancer. Cell Metab. 2015;22:577-589.
Not in our library10.1016/j.cmet.2015.08.007
160.
Papandreou I, et al. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187-197.
Not in our library10.1016/j.cmet.2006.01.012
161.
Gordan JD, et al. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 2007;11:335-347.
Not in our library10.1016/j.ccr.2007.02.006
162.
Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 2020;21:268-283.
Not in our library10.1038/s41580-020-0227-y
163.
Gupta VK, et al. Hypoxia-driven oncometabolite L-2HG maintains stemness-differentiation balance and facilitates immune evasion in pancreatic cancer. Cancer Res. 2021;81:4001-4013.
Not in our library10.1158/0008-5472.can-20-2562
164.
Faubert B, et al. Lactate metabolism in human lung tumors. Cell. 2017;171:358-371.e9.
Not in our library10.1016/j.cell.2017.09.019
165.
Emerging roles of lipid metabolism in cancer metastasis · 2017
No notice
166.
Furuta E, et al. Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1. Cancer Res. 2008;68:1003-1011.
Not in our library10.1158/0008-5472.can-07-2489
167.
Acetate functions as an epigenetic metabolite to promote lipid synthesis under hypoxia · 2016
No notice
168.
Ni T, et al. Oroxylin A suppresses the development and growth of colorectal cancer through reprogram of HIF1α-modulated fatty acid metabolism. Cell Death Dis. 2017;8:e2865.
Not in our library10.1038/cddis.2017.261
169.
Bauer DE, et al. ATP citrate lyase is an important component of cell growth and transformation. Oncogene. 2005;24:6314-6322.
Not in our library10.1038/sj.onc.1208773
170.
Lin J, et al. Hypoxia-induced miR-27 and miR-195 regulate ATP consumption, viability, and metabolism of rat cardiomyocytes by targeting PPARγ and FASN expression. Aging (Albany NY). 2021;13:10158-10174.
Not in our library10.18632/aging.202778
171.
Haraguchi M, et al. Snail modulates cell metabolism in MDCK cells. Biochem. Biophys. Res. Commun. 2013;432:618-625.
Not in our library10.1016/j.bbrc.2013.02.035
172.
ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via α-ketoglutarate. · 2015
Not checked
173.
Yoon H, et al. PHD3 loss promotes exercise capacity and fat oxidation in skeletal muscle. Cell Metab. 2020;32:215-228.e7.
Not in our library10.1016/j.cmet.2020.06.017
174.
German NJ, et al. PHD3 loss in cancer enables metabolic reliance on fatty acid oxidation via deactivation of ACC2. Mol. Cell. 2016;63:1006-1020.
Not in our library10.1016/j.molcel.2016.08.014
175.
Triglycerides Promote Lipid Homeostasis during Hypoxic Stress by Balancing Fatty Acid Saturation · 2018
No notice
176.
Lai KKY, et al. Stearoyl-CoA desaturase promotes liver fibrosis and tumor development in mice via a Wnt positive-signaling loop by stabilization of low-density lipoprotein-receptor-related proteins 5 and 6. Gastroenterology. 2017;152:1477-1491.
Not in our library10.1053/j.gastro.2017.01.021
177.
Tumor resistance to ferroptosis driven by Stearoyl-CoA Desaturase-1 (SCD1) in cancer cells and Fatty Acid Biding Protein-4 (FABP4) in tumor microenvironment promote tumor recurrence · 2021
Not checked
178.
Li J, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ. Res. 2005;97:698-706.
Not in our library10.1161/01.res.0000183879.60089.a9
179.
Melana JP, et al. The hypoxic microenvironment induces stearoyl-CoA desaturase-1 overexpression and lipidomic profile changes in clear cell renal cell carcinoma. Cancers. 2021;13:2962.
Not in our library10.3390/cancers13122962
180.
Zhang Y, et al. Positive feedback loop and synergistic effects between hypoxia-inducible factor-2α and stearoyl-CoA desaturase-1 promote tumorigenesis in clear cell renal cell carcinoma. Cancer Sci. 2013;104:416-422.
Not in our library10.1111/cas.12108
181.
Son J, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature. 2013;496:101-105.
Not in our library10.1038/nature12040
182.
Sun RC, Denko NC. Hypoxic regulation of glutamine metabolism through HIF1 and SIAH2 supports lipid synthesis that is necessary for tumor growth. Cell Metab. 2014;19:285-292.
Not in our library10.1016/j.cmet.2013.11.022
183.
Holleran AL, Briscoe DA, Fiskum G, Kelleher JK. Glutamine metabolism in AS-30D hepatoma cells. Evidence for its conversion into lipids via reductive carboxylation. Mol. Cell Biochem. 1995;152:95-101.
Not in our library10.1007/bf01076071
184.
Gameiro PA, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013;17:372-385.
Not in our library10.1016/j.cmet.2013.02.002
185.
Dennis EA, et al. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem. Rev. 2011;111:6130-6185.
Not in our library10.1021/cr200085w
186.
Kim K-S, et al. Hypoxia enhances lysophosphatidic acid responsiveness in ovarian cancer cells and lysophosphatidic acid induces ovarian tumor metastasis in vivo. Cancer Res. 2006;66:7983-7990.
Not in our library10.1158/0008-5472.can-05-4381
187.
Selvy PE, Lavieri RR, Lindsley CW, Brown HA. Phospholipase D: enzymology, functionality, and chemical modulation. Chem. Rev. 2011;111:6064-6119.
Not in our library10.1021/cr200296t
188.
Yao B, et al. Hypoxia-induced cofilin 1 promotes hepatocellular carcinoma progression by regulating the PLD1/AKT pathway. Clin. Transl. Med. 2021;11:e366.
Not in our library10.1002/ctm2.366
189.
Toschi A, et al. HIF alpha expression in VHL-deficient renal cancer cells is dependent on phospholipase D. Oncogene. 2008;27:2746-2753.
Not in our library10.1038/sj.onc.1210927
190.
Han S, et al. Phospholipase D activates HIF-1-VEGF pathway via phosphatidic acid. Exp. Mol. Med. 2014;46:e126.
Not in our library10.1038/emm.2014.86
191.
Rios-Colon L, et al. Carnitine palmitoyltransferase 1 regulates prostate cancer growth under hypoxia. Cancers. 2021;13:6302.
Not in our library10.3390/cancers13246302
192.
Zaugg K, et al. Carnitine palmitoyltransferase 1 C promotes cell survival and tumor growth under conditions of metabolic stress. Genes Dev. 2011;25:1041-1051.
Not in our library10.1101/gad.1987211
193.
HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism · 2017
No notice
194.
Ezzeddini R, et al. Downregulation of fatty acid oxidation by involvement of HIF-1α and PPARγ in human gastric adenocarcinoma and related clinical significance. J. Physiol. Biochem. 2021;77:249-260.
Not in our library10.1007/s13105-021-00791-3
195.
Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 1971;285:1182-1186.
Not in our library10.1056/nejm197111182852108
196.
Richard DE, Berra E, Pouyssegur J. Nonhypoxic pathway mediates the induction of hypoxia-inducible factor 1alpha in vascular smooth muscle cells. J. Biol. Chem. 2000;275:26765-26771.
Not in our library10.1016/s0021-9258(19)61441-9
197.
Xu T, et al. HIF-1alpha/VEGF pathway mediates 1,3,6,8-tetrabromo-9 H-carbazole-induced angiogenesis: a potential vascular toxicity of an emerging contaminant. J. Hazard Mater. 2022;432:128718.
Not in our library10.1016/j.jhazmat.2022.128718
198.
Wu C, et al. Injectable conductive and angiogenic hydrogels for chronic diabetic wound treatment. J. Control Release. 2022;344:249-260.
Not in our library10.1016/j.jconrel.2022.03.014
199.
Hlatky L, Tsionou C, Hahnfeldt P, Coleman CN. Mammary fibroblasts may influence breast tumor angiogenesis via hypoxia-induced vascular endothelial growth factor up-regulation and protein expression. Cancer Res. 1994;54:6083-6086.
Not in our library
200.
Seo SH, et al. Hypoxia-induced ELF3 promotes tumor angiogenesis through IGF1/IGF1R. EMBO Rep. 2022;23:e52977.
Not in our library10.15252/embr.202152977
201.
Amato R, et al. HIF-1-dependent induction of β3 adrenoceptor: evidence from the mouse retina. Cells. 2022;11:1271.
Not in our library10.3390/cells11081271
202.
Loss of HIF-1α in natural killer cells inhibits tumour growth by stimulating non-productive angiogenesis · 2017
No notice
203.
Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat. Rev. Drug Disco. 2011;10:417-427.
Not in our library10.1038/nrd3455
204.
Gao F, et al. Hypoxia-induced alterations in hyaluronan and hyaluronidase. Adv. Exp. Med. Biol. 2005;566:249-256.
Not in our library10.1007/0-387-26206-7_33
205.
Influence of hypoxia and neoangiogenesis on the growth of pancreatic cancer · 2003
Not checked
206.
Giatromanolaki A, et al. ‘Invading edge vs. inner’ (edvin) patterns of vascularization: an interplay between angiogenic and vascular survival factors defines the clinical behaviour of non-small cell lung cancer. J. Pathol. 2000;192:140-149.
Not in our library10.1002/1096-9896(2000)9999:9999<::aid-path693>3.0.co;2-r
207.
Wu Y, Biswas D, Swanton C. Impact of cancer evolution on immune surveillance and checkpoint inhibitor response. Semin Cancer Biol. 2022;84:89-102.
Not in our library10.1016/j.semcancer.2021.02.013
208.
Chouaib S, Noman MZ, Kosmatopoulos K, Curran MA. Hypoxic stress: obstacles and opportunities for innovative immunotherapy of cancer. Oncogene. 2017;36:439-445.
Not in our library10.1038/onc.2016.225
209.
The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia · 2021
No notice
210.
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399-408.
Not in our library10.1016/j.cell.2012.01.021
211.
Cramer T, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell. 2003;112:645-657.
Not in our library10.1016/s0092-8674(03)00154-5
212.
Walmsley SR, et al. Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J. Exp. Med. 2005;201:105-115.
Not in our library10.1084/jem.20040624
213.
Jantsch J, et al. Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 2008;180:4697-4705.
Not in our library10.4049/jimmunol.180.7.4697
214.
McNamee EN, Korns Johnson D, Homann D, Clambey ET. Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol. Res. 2013;55:58-70.
Not in our library10.1007/s12026-012-8349-8
215.
Takeda N, et al. Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev. 2010;24:491-501.
Not in our library10.1101/gad.1881410
216.
Finlay DK, et al. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 2012;209:2441-2453.
Not in our library10.1084/jem.20112607
217.
Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat. Rev. Immunol. 2005;5:844-852.
Not in our library10.1038/nri1710
218.
Maciver NJ, et al. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J. Leukoc. Biol. 2008;84:949-957.
Not in our library10.1189/jlb.0108024
219.
Cham CM, Gajewski TF. Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J. Immunol. 2005;174:4670-4677.
Not in our library10.4049/jimmunol.174.8.4670
220.
Cham CM, Driessens G, O’Keefe JP, Gajewski TF. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur. J. Immunol. 2008;38:2438-2450.
Not in our library10.1002/eji.200838289
221.
An HIF-1α/VEGF-A Axis in Cytotoxic T Cells Regulates Tumor Progression · 2017
No notice
222.
Lukashev D, et al. Differential regulation of two alternatively spliced isoforms of hypoxia-inducible factor-1 alpha in activated T lymphocytes. J. Biol. Chem. 2001;276:48754-48763.
Not in our library10.1074/jbc.m104782200
223.
Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell. 2011;146:772-784.
Not in our library10.1016/j.cell.2011.07.033
224.
Doedens AL, et al. Hypoxia-inducible factors enhance the effector responses of CD8(+) T cells to persistent antigen. Nat. Immunol. 2013;14:1173-1182.
Not in our library10.1038/ni.2714
225.
Sharma S, et al. Mitochondrial hypoxic stress induces widespread RNA editing by APOBEC3G in natural killer cells. Genome Biol. 2019;20:37.
Not in our library10.1186/s13059-019-1651-1
226.
Liikanen I, et al. Hypoxia-inducible factor activity promotes antitumor effector function and tissue residency by CD8 + T cells. J. Clin. Invest. 2021;131:e143729.
Not in our library10.1172/jci143729
227.
Lee JH, Elly C, Park Y, Liu Y-C. E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity. Immunity. 2015;42:1062-1074.
Not in our library10.1016/j.immuni.2015.05.016
228.
Melder RJ, et al. During angiogenesis, vascular endothelial growth factor and basic fibroblast growth factor regulate natural killer cell adhesion to tumor endothelium. Nat. Med. 1996;2:992-997.
Not in our library10.1038/nm0996-992
229.
Facciabene A, et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226-230.
Not in our library10.1038/nature10169
230.
Veliça P, et al. Modified hypoxia-inducible factor expression in CD8 T cells increases antitumor efficacy. Cancer Immunol. Res. 2021;9:401-414.
Not in our library10.1158/2326-6066.cir-20-0561
231.
Lukashev D, et al. Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J. Immunol. 2006;177:4962-4965.
Not in our library10.4049/jimmunol.177.8.4962
232.
Park JH, et al. Tumor hypoxia represses γδ T cell-mediated antitumor immunity against brain tumors. Nat. Immunol. 2021;22:336-346.
Not in our library10.1038/s41590-020-00860-7
233.
Robbins JR, et al. Hypoxia modulates early events in T cell receptor-mediated activation in human T lymphocytes via Kv1.3 channels. J. Physiol. 2005;564:131-143.
Not in our library10.1113/jphysiol.2004.081893
234.
Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy · 2022
No notice
235.
Hatfield SM, et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 2015;7:277ra230.
Not in our library10.1126/scitranslmed.aaa1260
236.
Nagaraj S, et al. Altered recognition of antigen is a mechanism of CD8+ T cell tolerance in cancer. Nat. Med. 2007;13:828-835.
Not in our library10.1038/nm1609
237.
Ohta A, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc. Natl Acad. Sci. USA. 2006;103:13132-13137.
Not in our library10.1073/pnas.0605251103
238.
Scharping NE, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 2021;22:205-215.
Not in our library10.1038/s41590-020-00834-9
239.
Zandberg DP, et al. Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck. J. Immunother. Cancer. 2021;9:e002088.
Not in our library10.1136/jitc-2020-002088
240.
Watson PH, et al. Carbonic anhydrase XII is a marker of good prognosis in invasive breast carcinoma. Br. J. Cancer. 2003;88:1065-1070.
Not in our library10.1038/sj.bjc.6600796
241.
Fischer K, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812-3819.
Not in our library10.1182/blood-2006-07-035972
242.
Zhang Y, et al. YYFZBJS inhibits colorectal tumorigenesis by enhancing Tregs-induced immunosuppression through HIF-1α mediated hypoxia in vivo and in vitro. Phytomedicine. 2022;98:153917.
Not in our library10.1016/j.phymed.2021.153917
243.
Konieczny P, et al. Interleukin-17 governs hypoxic adaptation of injured epithelium. Science. 2022;377:eabg9302.
Not in our library10.1126/science.abg9302
244.
Shi LZ, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 2011;208:1367-1376.
Not in our library10.1084/jem.20110278
245.
Wing K, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322:271-275.
Not in our library10.1126/science.1160062
246.
Deaglio S, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 2007;204:1257-1265.
Not in our library10.1084/jem.20062512
247.
Jarnicki AG, Lysaght J, Todryk S, Mills KHG. Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8 + regulatory T cells. J. Immunol. 2006;177:896-904.
Not in our library10.4049/jimmunol.177.2.896
248.
HIF-2α is indispensable for regulatory T cell function · 2020
No notice
249.
Sato E, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl Acad. Sci. USA. 2005;102:18538-18543.
Not in our library10.1073/pnas.0509182102
250.
Byrnes JR, et al. Hypoxia is a dominant remodeler of the effector T cell surface proteome relative to activation and regulatory T cell suppression. Mol. Cell Proteom. 2022;21:100217.
Not in our library10.1016/j.mcpro.2022.100217
251.
Sitkovsky MV. T regulatory cells: hypoxia-adenosinergic suppression and re-direction of the immune response. Trends Immunol. 2009;30:102-108.
Not in our library10.1016/j.it.2008.12.002
252.
EGFR-HIF1α signaling positively regulates the differentiation of IL-9 producing T helper cells · 2021
Not checked
253.
Li X, et al. miR-582 negatively regulates pre-B cell proliferation and survival through targeting Hif1α and Rictor. Cell Death Dis. 2022;13:107.
Not in our library10.1038/s41419-022-04560-y
254.
Burrows N, et al. Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development. Nat. Immunol. 2020;21:1408-1420.
Not in our library10.1038/s41590-020-0772-8
255.
Jellusova J, et al. Gsk3 is a metabolic checkpoint regulator in B cells. Nat. Immunol. 2017;18:303-312.
Not in our library10.1038/ni.3664
256.
Cho SH, et al. Germinal centre hypoxia and regulation of antibody qualities by a hypoxia response system. Nature. 2016;537:234-238.
Not in our library10.1038/nature19334
257.
Bos R, et al. Protein expression of B-cell lymphoma gene 6 (BCL-6) in invasive breast cancer is associated with cyclin D1 and hypoxia-inducible factor-1alpha (HIF-1alpha). Oncogene. 2003;22:8948-8951.
Not in our library10.1038/sj.onc.1206995
258.
Jang J-W, Thuy PX, Lee J-W, Moon E-Y. CXCR4 promotes B cell viability by the cooperation of nuclear factor (erythroid-derived 2)-like 2 and hypoxia-inducible factor-1α under hypoxic conditions. Cell Death Dis. 2021;12:330.
Not in our library10.1038/s41419-021-03615-w
259.
Hennequin A, et al. Tumor infiltration by Tbet+ effector T cells and CD20 + B cells is associated with survival in gastric cancer patients. Oncoimmunology. 2016;5:e1054598.
Not in our library10.1080/2162402x.2015.1054598
260.
Muthalagu N, et al. Repression of the Type I Interferon Pathway Underlies MYC- and KRAS-Dependent Evasion of NK and B Cells in Pancreatic Ductal Adenocarcinoma. Cancer Disco. 2020;10:872-887.
Not in our library10.1158/2159-8290.cd-19-0620
261.
Shrestha B, et al. B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes. J. Immunol. 2010;184:4819-4826.
Not in our library10.4049/jimmunol.0903063
262.
Gunderson AJ, et al. Bruton Tyrosine Kinase-Dependent Immune Cell Cross-talk Drives Pancreas Cancer. Cancer Disco. 2016;6:270-285.
Not in our library10.1158/2159-8290.cd-15-0827
263.
Ammirante M, et al. Tissue injury and hypoxia promote malignant progression of prostate cancer by inducing CXCL13 expression in tumor myofibroblasts. Proc. Natl Acad. Sci. USA. 2014;111:14776-14781.
Not in our library10.1073/pnas.1416498111
264.
Le A, et al. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab. 2012;15:110-121.
Not in our library10.1016/j.cmet.2011.12.009
265.
Sander S, et al. Synergy between PI3K signaling and MYC in Burkitt lymphomagenesis. Cancer Cell. 2012;22:167-179.
Not in our library10.1016/j.ccr.2012.06.012
266.
Hypoxia-inducible factor-1α is a critical transcription factor for IL-10-producing B cells in autoimmune disease · 2018
No notice
267.
Shen P, et al. IL-35-producing B cells are critical regulators of immunity during autoimmune and infectious diseases. Nature. 2014;507:366-370.
Not in our library10.1038/nature12979
268.
Wang J, et al. Novel mechanism of macrophage-mediated metastasis revealed in a zebrafish model of tumor development. Cancer Res. 2015;75:306-315.
Not in our library10.1158/0008-5472.can-14-2819
269.
Zhang Y, et al. Hypoxia enhances IL-10-producing B cell generation through upregulating high-mobility group B1 on tumor cell-released autophagosomes. Immunol. Lett. 2019;216:36-42.
Not in our library10.1016/j.imlet.2019.09.005
270.
Turnis ME, et al. Interleukin-35 Limits Anti-Tumor. Immunity Immunity. 2016;44:316-329.
Not in our library10.1016/j.immuni.2016.01.013
271.
Sawant DV, et al. Adaptive plasticity of IL-10 and IL-35 T cells cooperatively promotes tumor T cell exhaustion. Nat. Immunol. 2019;20:724-735.
Not in our library10.1038/s41590-019-0346-9
272.
Conter LJ, Song E, Shlomchik MJ, Tomayko MM. CD73 expression is dynamically regulated in the germinal center and bone marrow plasma cells are diminished in its absence. PLoS One. 2014;9:e92009.
Not in our library10.1371/journal.pone.0092009
273.
Zhang F, et al. Specific Decrease in B-Cell-Derived Extracellular Vesicles Enhances Post-Chemotherapeutic CD8 T Cell Responses. Immunity. 2019;50:738-750.e7.
Not in our library10.1016/j.immuni.2019.01.010
274.
Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev. Immunol. 2012;30:221-241.
Not in our library10.1146/annurev-immunol-020711-074934
275.
Kaelin WG. Common pitfalls in preclinical cancer target validation. Nat. Rev. Cancer. 2017;17:425-440.
Not in our library10.1038/nrc.2017.32
276.
Lee KE, et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Disco. 2016;6:256-269.
Not in our library10.1158/2159-8290.cd-15-0822
277.
Lee KE, et al. Hif1α deletion limits tissue regeneration via aberrant B cell accumulation in experimental pancreatitis. Cell Rep. 2018;23:3457-3464.
Not in our library10.1016/j.celrep.2018.05.071
278.
Kim R, et al. Early tumor-immune microenvironmental remodeling and response to first-line fluoropyrimidine and platinum chemotherapy in advanced gastric cancer. Cancer Disco. 2022;12:984-1001.
Not in our library10.1158/2159-8290.cd-21-0888
279.
Dong F, et al. ALKBH5 facilitates hypoxia-induced paraspeckle assembly and IL8 secretion to generate an immunosuppressive tumor microenvironment. Cancer Res. 2021;81:5876-5888.
Not in our library10.1158/0008-5472.can-21-1456
280.
Chaturvedi P, Gilkes DM, Takano N, Semenza GL. Hypoxia-inducible factor-dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment. Proc. Natl Acad. Sci. USA. 2014;111:E2120-E2129.
Not in our library10.1073/pnas.1406655111
281.
Granulocytic Myeloid‐Derived Suppressor Cells Promote the Stemness of Colorectal Cancer Cells through Exosomal S100A9 · 2019
No notice
282.
Vitale I, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36-50.
Not in our library10.1016/j.cmet.2019.06.001
283.
Mantovani A, et al. Tumour-associated macrophages as treatment targets in oncology. Nat. Rev. Clin. Oncol. 2017;14:399-416.
Not in our library10.1038/nrclinonc.2016.217
284.
Chen X-J, et al. A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner. Angiogenesis. 2021;24:549-565.
Not in our library10.1007/s10456-020-09766-2
285.
Piao H, et al. A positive feedback loop between gastric cancer cells and tumor-associated macrophage induces malignancy progression. J. Exp. Clin. Cancer Res. 2022;41:174.
Not in our library10.1186/s13046-022-02366-6
286.
Ruffell B, Coussens LM. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462-472.
Not in our library10.1016/j.ccell.2015.02.015
287.
Cowman SJ, et al. Macrophage HIF-1α is an independent prognostic indicator in kidney cancer. Clin. Cancer Res. 2020;26:4970-4982.
Not in our library10.1158/1078-0432.ccr-19-3890
288.
Blouin CC, Pagé EL, Soucy GM, Richard DE. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood. 2004;103:1124-1130.
Not in our library10.1182/blood-2003-07-2427
289.
Jeny F, et al. Hypoxia promotes a mixed inflammatory-fibrotic macrophages phenotype in active sarcoidosis. Front Immunol. 2021;12:719009.
Not in our library10.3389/fimmu.2021.719009
290.
Doedens AL, et al. Macrophage expression of hypoxia-inducible factor-1 alpha suppresses T-cell function and promotes tumor progression. Cancer Res. 2010;70:7465-7475.
Not in our library10.1158/0008-5472.can-10-1439
291.
Graham C, et al. Mechanisms of hypoxia-induced immune escape in cancer and their regulation by nitric oxide. Redox Biol. 2015;5:417.
Not in our library10.1016/j.redox.2015.09.022
292.
Melillo G, et al. A hypoxia-responsive element mediates a novel pathway of activation of the inducible nitric oxide synthase promoter. J. Exp. Med. 1995;182:1683-1693.
Not in our library10.1084/jem.182.6.1683
293.
Zhang W, et al. Crosstalk between IL-15Rα tumor-associated macrophages and breast cancer cells reduces CD8 T cell recruitment. Cancer Commun. (Lond.). 2022;42:536-557.
Not in our library10.1002/cac2.12311
294.
Malier M, et al. Hypoxia drives dihydropyrimidine dehydrogenase expression in macrophages and confers chemoresistance in colorectal cancer. Cancer Res. 2021;81:5963-5976.
Not in our library10.1158/0008-5472.can-21-1572
295.
Onita T, et al. Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer. Clin. Cancer Res. 2002;8:471-480.
Not in our library
296.
Colegio OR, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559-563.
Not in our library10.1038/nature13490
297.
Chiu DK-C, et al. Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26. Hepatology. 2016;64:797-813.
Not in our library10.1002/hep.28655
298.
Xu Y, et al. PINK1 deficiency in gastric cancer compromises mitophagy, promotes the Warburg effect, and facilitates M2 polarization of macrophages. Cancer Lett. 2022;529:19-36.
Not in our library10.1016/j.canlet.2021.12.032
299.
Zhang D, et al. Metabolic regulation of gene expression by histone lactylation. Nature. 2019;574:575-580.
Not in our library10.1038/s41586-019-1678-1
300.
Oberg HH, et al. Tribody [(HER2)xCD16] is more effective than trastuzumab in enhancing γδ T cell and natural killer cell cytotoxicity against HER2-expressing cancer cells. Front Immunol. 2018;9:814.
Not in our library10.3389/fimmu.2018.00814
301.
Rodig SJ, et al. MHC proteins confer differential sensitivity to CTLA-4 and PD-1 blockade in untreated metastatic melanoma. Sci. Transl. Med. 2018;10:eaar3342.
Not in our library10.1126/scitranslmed.aar3342
302.
Wang S, et al. Blocking CD47 promotes antitumour immunity through CD103 dendritic cell-NK cell axis in murine hepatocellular carcinoma model. J. Hepatol. 2022;77:467-478.
Not in our library10.1016/j.jhep.2022.03.011
303.
André P, et al. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK cells. Cell. 2018;175:1731-1743.e13.
Not in our library10.1016/j.cell.2018.10.014
304.
Hypoxia Induced Impairment of NK Cell Cytotoxicity against Multiple Myeloma Can Be Overcome by IL-2 Activation of the NK Cells · 2013
No notice
305.
Sobecki M, et al. NK cells in hypoxic skin mediate a trade-off between wound healing and antibacterial defence. Nat. Commun. 2021;12:4700.
Not in our library10.1038/s41467-021-25065-w
306.
Ormiston ML, et al. Impaired natural killer cell phenotype and function in idiopathic and heritable pulmonary arterial hypertension. Circulation. 2012;126:1099-1109.
Not in our library10.1161/circulationaha.112.110619
307.
Cui C, et al. Hypoxia-inducible gene 2 promotes the immune escape of hepatocellular carcinoma from nature killer cells through the interleukin-10-STAT3 signaling pathway. J. Exp. Clin. Cancer Res. 2019;38:229.
Not in our library10.1186/s13046-019-1233-9
308.
Messai Y, et al. ITPR1 protects renal cancer cells against natural killer cells by inducing autophagy. Cancer Res. 2014;74:6820-6832.
Not in our library10.1158/0008-5472.can-14-0303
309.
Viry E, et al. Autophagic degradation of GZMB/granzyme B: a new mechanism of hypoxic tumor cell escape from natural killer cell-mediated lysis. Autophagy. 2014;10:173-175.
Not in our library10.4161/auto.26924
310.
Reid MD, et al. Tumor-infiltrating neutrophils in pancreatic neoplasia. Mod. Pathol. 2011;24:1612-1619.
Not in our library10.1038/modpathol.2011.113
311.
Sadiku P, et al. Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metab. 2021;33:1062-1064.
Not in our library10.1016/j.cmet.2021.03.018
312.
Watts ER, et al. Hypoxia drives murine neutrophil protein scavenging to maintain central carbon metabolism. J. Clin. Invest. 2021;131:e134073.
Not in our library10.1172/jci134073
313.
Gentles AJ, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat. Med. 2015;21:938-945.
Not in our library10.1038/nm.3909
314.
NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma · 2015
Corrected
315.
Neutrophils mediate Salmonella Typhimurium clearance through the GBP4 inflammasome-dependent production of prostaglandins · 2016
No notice
316.
Westphal K, et al. Containment of tumor-colonizing bacteria by host neutrophils. Cancer Res. 2008;68:2952-2960.
Not in our library10.1158/0008-5472.can-07-2984
317.
Tian S, et al. Tumour-associated neutrophils secrete AGR2 to promote colorectal cancer metastasis via its receptor CD98hc-xCT. Gut. 2022;71:2489-2501.
Not in our library10.1136/gutjnl-2021-325137
318.
Steele CW, et al. CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell. 2016;29:832-845.
Not in our library10.1016/j.ccell.2016.04.014
319.
Wang, L. et al. Single-cell RNA-seq analysis reveals BHLHE40-driven pro-tumour neutrophils with hyperactivated glycolysis in pancreatic tumour microenvironment. Gut0, 1–14 (2022)..
Not in our library10.1136/gutjnl-2021-326070
320.
Willson JA, et al. Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle. Blood. 2022;139:281-286.
Not in our library10.1182/blood.2021011010
321.
Zhang Y, et al. Neutrophil cyto-pharmaceuticals suppressing tumor metastasis via inhibiting hypoxia-inducible factor-1α in circulating breast cancer cells. Adv. Health. Mater. 2022;11:e2101761.
Not in our library10.1002/adhm.202101761
322.
Monceaux V, et al. Anoxia and glucose supplementation preserve neutrophil viability and function. Blood. 2016;128:993-1002.
Not in our library10.1182/blood-2015-11-680918
323.
Blaisdell A, et al. Neutrophils oppose uterine epithelial carcinogenesis via debridement of hypoxic tumor cells. Cancer Cell. 2015;28:785-799.
Not in our library10.1016/j.ccell.2015.11.005
324.
Mahiddine K, et al. Relief of tumor hypoxia unleashes the tumoricidal potential of neutrophils. J. Clin. Invest. 2020;130:389-403.
Not in our library10.1172/jci130952
325.
Chafe SC, et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production. Cancer Res. 2015;75:996-1008.
Not in our library10.1158/0008-5472.can-14-3000
326.
Hong J, et al. Role of tumor pericytes in the recruitment of myeloid-derived suppressor cells. J. Natl Cancer Inst. 2015;107:djv209.
Not in our library10.1093/jnci/djv209
327.
Horikawa N, et al. Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. Br. J. Cancer. 2020;122:778-788.
Not in our library10.1038/s41416-019-0725-x
328.
Gunda V, et al. Anti-PD-1/PD-L1 therapy augments lenvatinib’s efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer. Int J. Cancer. 2019;144:2266-2278.
Not in our library10.1002/ijc.32041
329.
Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma · 2017
No notice
330.
Noman MZ, et al. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 2014;211:781-790.
Not in our library10.1084/jem.20131916
331.
Corzo CA, et al. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 2010;207:2439-2453.
Not in our library10.1084/jem.20100587
332.
Noman MZ, et al. Tumor-promoting effects of myeloid-derived suppressor cells are potentiated by hypoxia-induced expression of miR-210. Cancer Res. 2015;75:3771-3787.
Not in our library10.1158/0008-5472.can-15-0405
333.
CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer · 2017
Not checked
334.
Wang Y, et al. Hypoxia and TGF-β1 lead to endostatin resistance by cooperatively increasing cancer stem cells in A549 transplantation tumors. Cell Biosci. 2015;5:72.
Not in our library10.1186/s13578-015-0064-4
335.
Guo X, et al. Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid-derived suppressor cells via the miR-10a/Rora and miR-21/Pten pathways. Oncogene. 2018;37:4239-4259.
Not in our library10.1038/s41388-018-0261-9
336.
Liu G, et al. SIRT1 limits the function and fate of myeloid-derived suppressor cells in tumors by orchestrating HIF-1α-dependent glycolysis. Cancer Res. 2014;74:727-737.
Not in our library10.1158/0008-5472.can-13-2584
337.
Yu Q, Dong L, Li Y, Liu G. SIRT1 and HIF1α signaling in metabolism and immune responses. Cancer Lett. 2018;418:20-26.
Not in our library10.1016/j.canlet.2017.12.035
338.
Guo X, et al. Glioma exosomes mediate the expansion and function of myeloid-derived suppressor cells through microRNA-29a/Hbp1 and microRNA-92a/Prkar1a pathways. Int J. Cancer. 2019;144:3111-3126.
Not in our library10.1002/ijc.32052
339.
Jacquelot N, Seillet C, Vivier E, Belz GT. Innate lymphoid cells and cancer. Nat. Immunol. 2022;23:371-379.
Not in our library10.1038/s41590-022-01127-z
340.
Vivier E, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174:1054-1066.
Not in our library10.1016/j.cell.2018.07.017
341.
Salimi M, et al. Activated innate lymphoid cell populations accumulate in human tumour tissues. BMC Cancer. 2018;18:341.
Not in our library10.1186/s12885-018-4262-4
342.
Moral JA, et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature. 2020;579:130-135.
Not in our library10.1038/s41586-020-2015-4
343.
Ren G, et al. Transcription factors TCF-1 and GATA3 are key factors for the epigenetic priming of early innate lymphoid progenitors toward distinct cell fates. Immunity. 2022;55:1402-1413.
Not in our library10.1016/j.immuni.2022.06.019
344.
Heinrich B, et al. The tumour microenvironment shapes innate lymphoid cells in patients with hepatocellular carcinoma. Gut. 2022;71:1161-1175.
Not in our library10.1136/gutjnl-2021-325288
345.
Li Z, et al. ILC1s control leukemia stem cell fate and limit development of AML. Nat. Immunol. 2022;23:718-730.
Not in our library10.1038/s41590-022-01198-y
346.
Kansler ER, et al. Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies. Nat. Immunol. 2022;23:904-915.
Not in our library10.1038/s41590-022-01213-2
347.
Song J, et al. Requirement of RORα for maintenance and antitumor immunity of liver-resident natural killer cells/ILC1s. Hepatology. 2022;75:1181-1193.
Not in our library10.1002/hep.32147
348.
Kim J, et al. Intratumorally establishing type 2 innate lymphoid cells blocks tumor growth. J. Immunol. 2016;196:2410-2423.
Not in our library10.4049/jimmunol.1501730
349.
Ye L, et al. Hypoxia-reprogrammed regulatory group 2 innate lymphoid cells promote immunosuppression in pancreatic cancer. EBioMedicine. 2022;79:104016.
Not in our library10.1016/j.ebiom.2022.104016
350.
Jou E, et al. An innate IL-25-ILC2-MDSC axis creates a cancer-permissive microenvironment for mutation-driven intestinal tumorigenesis. Sci. Immunol. 2022;7:eabn0175.
Not in our library10.1126/sciimmunol.abn0175
351.
Goc J, et al. Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer. Cell. 2021;184:5015-5030.
Not in our library10.1016/j.cell.2021.07.029
352.
Bruchard M, et al. Recruitment and activation of type 3 innate lymphoid cells promote antitumor immune responses. Nat. Immunol. 2022;23:262-274.
Not in our library10.1038/s41590-021-01120-y
353.
Gronke K, et al. Interleukin-22 protects intestinal stem cells against genotoxic stress. Nature. 2019;566:249-253.
Not in our library10.1038/s41586-019-0899-7
354.
Wilson RE, Keng PC, Sutherland RM. Drug resistance in Chinese hamster ovary cells during recovery from severe hypoxia. J. Natl Cancer Inst. 1989;81:1235-1240.
Not in our library10.1093/jnci/81.16.1235
355.
Skarsgard LD, Vinczan A, Skwarchuk MW, Chaplin DJ. The effect of low pH and hypoxia on the cytotoxic effects of SR4233 and mitomycin C in vitro. Int J. Radiat. Oncol. Biol. Phys. 1994;29:363-367.
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356.
Yokoi K, Fidler IJ. Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine. Clin. Cancer Res. 2004;10:2299-2306.
Not in our library10.1158/1078-0432.ccr-03-0488
357.
Sakata K, et al. Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance. Br. J. Cancer. 1991;64:809-814.
Not in our library10.1038/bjc.1991.405
358.
Pinzón-Daza ML, et al. Oxidative stress promotes doxorubicin-induced Pgp and BCRP expression in colon cancer cells under hypoxic conditions. J. Cell Biochem. 2017;118:1868-1878.
Not in our library10.1002/jcb.25890
359.
Lv Y, et al. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer. Onco Targets Ther. 2015;8:1941-1948.
Not in our library10.2147/ott.s82835
360.
Geller LT, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357:1156-1160.
Not in our library10.1126/science.aah5043
361.
El-Gebali S, Bentz S, Hediger MA, Anderle P. Solute carriers (SLCs) in cancer. Mol. Asp. Med. 2013;34:719-734.
Not in our library10.1016/j.mam.2012.12.007
362.
Gao X-Z, et al. Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion, epithelial-mesenchymal transition, and chemotherapy resistance in non-small-cell lung cancer. J. Cell Physiol. 2019;234:15035-15043.
Not in our library10.1002/jcp.28144
363.
Wang K, et al. Interleukin-6 contributes to chemoresistance in MDA-MB-231 cells via targeting HIF-1α. J. Biochem. Mol. Toxicol. 2018;32:e22039.
Not in our library10.1002/jbt.22039
364.
Okazaki M, et al. The effect of HIF-1α and PKM1 expression on acquisition of chemoresistance. Cancer Manag Res. 2018;10:1865-1874.
Not in our library10.2147/cmar.s166136
365.
Taniguchi K, et al. PKM1 is involved in resistance to anti-cancer drugs. Biochem. Biophys. Res. Commun. 2016;473:174-180.
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