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NK cell exhaustion in the tumor microenvironment

Hao Jia, Hongmei Yang, Huaxing Xiong and 1 more

Frontiers in Immunology · 2023 · Review · CC BY

doi:10.3389/fimmu.2023.1303605

Abstract

Natural killer (NK) cells kill mutant cells through death receptors and cytotoxic granules, playing an essential role in controlling cancer progression. However, in the tumor microenvironment (TME), NK cells frequently exhibit an exhausted status, which impairs their immunosurveillance function and contributes to tumor immune evasion. Emerging studies are ongoing to reveal the properties and mechanisms of NK cell exhaustion in the TME. In this review, we will briefly introduce the maturation, localization, homeostasis, and cytotoxicity of NK cells. We will then summarize the current understanding of the main mechanisms underlying NK cell exhaustion in the TME in four aspects: dysregulation of inhibitory and activating signaling, tumor cell-derived factors, immunosuppressive cells, and metabolism and exhaustion. We will also discuss the therapeutic approaches currently being developed to reverse NK cell exhaustion and enhance NK cell cytotoxicity in the TME.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Natural killer (NK) cells are an important component of the innate immune system and play a critical role in controlling malignancies and viral infections. Unlike T cells, NK cells kill tumor and virus-infected cells without antigen presentation, allowing NK cells to elicit a rapid immune response. NK cell-based therapies are currently being developed for the treatment of blood cancers as well as various solid tumors. However, in the tumor microenvironment (TME), NK cells always exhibit an exhausted state, which facilitates the immune escape of tumor cells and reduces the efficacy of NK cell-based therapies. The main features of NK cell exhaustion include impaired cytotoxicity, decreased secretion of cytokines, upregulated expression of inhibitory receptors, downregulated expression of activating receptors, dysregulation of proliferation, and metabolic dysfunction. In recent years, the mechanisms of NK cell exhaustion have been intensively studied, although the exact mechanisms have not been fully elucidated. In this review, we summarize the current understanding of the mechanisms of NK cell exhaustion in the TME.

NK cell maturation, localization, homeostasis, and cytotoxicity

NK cells arise from hematopoietic stem cells in the bone marrow. Mouse NK cells develop mainly in the bone marrow, whereas human NK cells can develop in the bone marrow as well as in other lymphoid tissues such as the thymus, spleen, lymph nodes, and liver. Mouse NK cells are defined as CD3− NK1.1+ cells and can be classified into four types based on the presence of two markers, CD27 and CD11b, to indicate their maturation stages. CD27− CD11b− NK cells are immature NK cells with high differentiation potential. These NK cells differentiate into CD27+ CD11b− NK cells and then further develop into CD27+ CD11b+ NK cells that can migrate from bone marrow to peripheral tissues. CD27− CD11b+ NK cells are the mature NK cells with high cytotoxicity. Human NK cells are defined as CD3– CD56+ cells and can be further divided into two types: CD56bright CD16– and CD56dim CD16+ cells. CD56bright CD16– NK cells account for only 5-10% of NK cells and are less mature and less cytotoxic. They are thought to be the precursors of CD56dim CD16+ NK cells, i.e., mature NK cells. CD56dim CD16+ NK cells account for 90% of NK cells and have higher cytotoxicity.

NK cells are widely distributed in various tissues and organs of mammals. In recent decades, studies have shown that NK cells are mainly found in bone marrow, peripheral blood, liver, lung, spleen, and uterus. In addition, there are also significant numbers of NK cells in lymph nodes, thymus, mucosa-associated lymphoid tissues, skin, and kidney. In peripheral blood, 5-20% of lymphocytes are NK cells. In the liver, NK cells are enriched in the hepatic sinusoids. In mice, NK cells account for 5-10% of liver lymphocytes, whereas this proportion can reach 30-50% in humans. In the lung, NK cells can account for approximately 10-20% of total lymphocytes. Although NK cells account for only 2-4% of splenic lymphocytes in mice, their absolute number is quite high. NK cells in utero are specialized NK cells that can make up 70% of lymphocytes at the maternal-fetal interface.

Adequate numbers of NK cells in peripheral tissues are important for normal immune surveillance function. NK cells are continuously produced by development and differentiation from hematopoietic stem cells in the bone marrow and are replenished to peripheral tissues to replace dead NK cells. Previously, mature NK cells were thought to have low proliferation ability. However, recent studies have shown that mature NK cells, similar to T cells, can undergo homeostatic proliferation to contribute to maintaining their numbers in peripheral tissues. This homeostatic proliferation depends on stimulation by several cytokines, including IL-2 and IL-15. NK cells even have some memory properties similar to those of long-lived CD8+ T cells, and this immune memory can be maintained for several weeks to months. After re-stimulation by antigens, these long-lived memory NK cells rapidly proliferate and kill target cells.

Unlike CD8+ T cells, NK cell activation does not require antigen presentation but depends on the dynamic balance of activating and inhibitory signals from target cells, including cancer cells and infected cells. Cancer cells can escape the killing from cytotoxic T cells by downregulating the expression of MHC I molecules. However, this reduction of MHC I molecules on the surface of cancer cells triggers the activation of NK cells. NK cells kill cancer cells mainly via four approaches. First, NK cells express FasL and TRAIL on the cell surface, which can bind to the corresponding receptors Fas and TRAILR on cancer cells, respectively. This binding triggers the activation of caspase-8 and, subsequently, caspase-3, leading to the apoptosis of target cells. Second, NK cells release various cytotoxic granules such as perforin and granzyme B to induce lysis and apoptosis of tumor cells. Third, the Fcγ receptor III or CD16 on NK cells can recognize the antibodies binding to cancer cells, which induces NK cells to produce more cytotoxic granules to eliminate cancer cells, an effect called antibody-dependent cell-mediated cytotoxicity (ADCC). Fourth, NK cells can also secrete IFNγ to induce cancer cell death and regulate other cancer-fighting immune cells.

Dysregulation of inhibitory and activating signaling

The control of NK cell activation is a balance between signals from inhibitory receptors (such as KIR, PD-1, TIGIT, TIM-3, LAG-3, NKG2A, CD96, IL-1R8, and KLRG1) and activating receptors (such as NKG2D, CD16, CD226, NKp30, NKp44, and NKp46). In the TME, inhibitory receptors on NK cells and their ligands on tumor cells are always upregulated, whereas activating receptors and ligands are downregulated ( Figure 1 ). For example, in ovarian cancer patients, the percentage of PD-1+ NK cells in peripheral blood was much higher than in healthy individuals. When PD-L1 expressed on the surface of tumor cells bound to PD-1 on NK cells, an exhausted phenotype and even apoptotic cell death were induced in NK cells. TIGIT is a co-inhibitory receptor expressed on NK cells, and the major ligand for TIGIT is CD155. NK cells in intratumoral regions showed significantly higher expression of TIGIT than the NK cells in peritumoral regions. The binding of CD155, expressed on tumor cells, to TIGIT on the surface of NK cells reduced the expression levels of IFNγ and the death ligand TRAIL by NK cells. TIM3 is a maturation marker for NK cells, and upregulation of TIM-3 was found in several cancers, including lung, colorectal, and gastric cancer. At least four ligands for TIM-3 have been found, including galectin-9, CD66a, phosphatidylserine, and HMGB1. The interaction between galectin-9 and TIM-3 was thought to suppress NK cell-mediated cytotoxicity in tumor tissues. However, some other studies suggested that galectin-9 might enhance NK cell activity. NKG2D is a potent activating receptor expressed on the surface of NK cells. In hepatocellular carcinoma patients, a much higher DNA methylation frequency in the NKG2D promoter region was detected. Downregulation of NKG2D on NK cells was found in various cancers such as glioma, leukemia, head and neck cancer, and cervical cancer and contributed to the decreased activity of NK cells.

Tumor cell-derived factors

Tumor cells can secrete various factors that inhibit NK cell activity ( Figure 1 ). The binding of MICA/B on tumor cells and NKG2D on NK cells activates NK cells. However, several studies showed that tumor cells also produced and shed soluble MICA/B proteins that could bind to NKG2D and inhibit NK cell activation and cytotoxicity by mechanisms that are still not fully elucidated. Tumor cells secreted PGE2 to inhibit the killing effects of NK cells by decreasing the levels of NK receptors such as NKp30, NKp44, and NKG2D. In addition, PGE2 also reduced the killing effects of NK cells by suppressing IFNγ production. TGF-β is an important immunosuppressive factor in balancing the immune response. Not surprisingly, tumor cells can secrete TGF-β to inhibit NK cell activation and cytotoxicity. Some studies revealed that extracellular adenosine levels were increased in the TME, which could inhibit degranulation and cytokine production by NK cells. IL-10 is an important immunoregulatory cytokine with both protumoral and antitumoral effects. In its immunosuppressive role, IL-10 suppresses the expression of NKG2D ligands and increases the expression of inhibitory ligands on tumor cells to inhibit the activation and killing effects of NK cells. Some studies showed that IL-10 could also enhance the activities of NK cells. CD155 is a ligand for both activating and inhibitory receptors expressed on NK cells. The soluble form of CD155 secreted by melanoma cells was found to inhibit NK cell degranulation and cytotoxicity. Tumor cell-derived extracellular vesicles or exosomes can both activate and inhibit NK cell function, depending on the properties of the exosomes. Several studies have shown that tumor cells produce exosomes containing NKG2D ligands and TGF-β, which can impair NK cell proliferation and cytotoxicity. Tumor cells can also generate exosomes containing noncoding RNAs such as miR-92b, SNHG10, and circUHRF1 to inhibit NK cell activity in the TME.

Immunosuppressive cells

In the TME, there are a number of cells in addition to tumor cells and NK cells ( Figure 1 ). CD4+CD25+ regulatory T cells (Tregs), as immunosuppressive cells, impaired the proliferation and IFNγ production of NK cells through TGF-β signaling. Myeloid-derived suppressor cells (MDSCs) in the TME could also inhibit NK cell activity through membrane-bound TGF-β, which decreased the expression levels of NKG2D and IFNγ in NK cells. MDSCs increased the level of arginase-1, which reduced IFNγ production but did not affect granzyme B release or NK cell viability. In clinical patients with hepatocellular carcinoma, MDSCs mediated the suppression of NK cells through NKp30. Nitric oxide produced by MDSCs inhibited NK cell cytotoxicity by impairing the ADCC response. Tumor-associated macrophages (TAMs) play an important role in tumor immune evasion. Several studies showed that TAMs induced NK cell dysfunction through secretion of TGF-β. TAMs also inhibited NK cell activity by expressing CD80 and CD86, which bound to CTLA-4 on NK cells. In addition, immunosuppressive chemokine ligands such as CCL5 and CCL22 secreted by TAMs could recruit Tregs to the TME, further suppressing the killing effects of NK cells. There are sufficient numbers of neutrophils in the TME to interfere with NK cell activity. For example, neutrophils reduced the expression of CCR1 on NK cells, which could reduce the infiltration of NK cells into tumor tissues. The PD-L1 molecules on neutrophils bound to PD-1 receptors on the surface of NK cells, reducing the amount of IFNγ expressed by NK cells. Neutrophils could also release ROS and cathepsin G to inhibit NK cell cytotoxicity. In addition to immune cells, tumor stromal cells have been suggested to inhibit the proliferation of NK cells and suppress the expression of NKp44 and NKp46 on NK cells. While mesenchymal stromal cells (MSCs) initially promoted NK cell function by releasing type I interferon, they later induced NK cell dysfunction by secreting TGF-β and IL-6, ultimately leading to NK cell senescence.

Metabolism and exhaustion

Because of their unique metabolic properties, solid tumor cells generate various metabolic stresses such as nutrient depletion, low oxygen, low pH, and accumulation of waste products in the TME. These stresses not only affect the tumor cells but also severely impair the activity of NK cells in the TME ( Figure 1 ). Adequate energy supply is important for proliferation, survival, and cytotoxicity of NK cells. Some studies suggested that steady-state NK cells preferred oxidative phosphorylation (OXPHOS) for ATP production, whereas activated NK cells relied more on glycolysis. Disruption of either glycolysis or OXPHOS may impair NK cell function. Lung tumor cells secreted TGF-β in the TME, which upregulated the expression of fructose-1,6-bisphosphatase in NK cells, resulting in inhibition of glycolysis and decreased cytotoxicity and viability of NK cells. In melanoma, inhibition of Srebp activity led to a decrease in cytokine-enhanced glycolysis and OXPHOS in NK cells, which impaired the effector function of NK cells. Inhibition of glycolysis and OXPHOS could decrease the secretion of IFNγ by NK cells and attenuate their cytotoxicity to leukemia cells.

Hypoxia in the TME contributes to cancer cells escaping NK cells’ killing and developing into advanced tumors. Hypoxia inhibited the expression of heat shock protein 70 and MICA/B of tumor cells, which helped tumor cells escape recognition by NK cells. In multiple myeloma, hypoxia inhibited the expression of perforin and granzyme B by NK cells, impairing NK cell cytotoxicity. Hypoxia led to the upregulation of HIF-1ɑ and downregulation of NK cell activating receptors such as NKG2D and natural cytotoxicity receptors. In addition to NK cells, hypoxia-induced HIF-1ɑ could also increase the expression of PD-L1 on MDSCs, leading to the suppression of T cells. A liver cancer study showed that hypoxia induced activation of mTOR-Drp1 proteins in the tumor-infiltrating NK cells, leading to increased mitochondrial fragmentation in these NK cells. As a result, tumor-infiltrating NK cells exhibited lower cytotoxicity and were more prone to cell death compared with NK cells in tumor-adjacent tissues.

Most tumor cells rely on aerobic glycolysis for energy production, which is known as the “Warburg effect,” producing a large amount of lactate as a waste product. Several studies have found that lactate can lead to the acidification of the TME and impair NK cell activity. For example, melanoma cells highly expressed lactate dehydrogenase, an enzyme that catalyzes lactate synthesis from pyruvate, and the accumulation of lactate in melanomas decreased the number of NK cells and inhibited cytokine production by NK cells. To form liver metastases, colorectal cancer cells inhibited the function of liver-resident NK cells by secreting lactate, which lowered pH and damaged mitochondria inside NK cells.

Lipid metabolism is critical to the effector function of NK cells. A study showed that obesity-induced accumulation of lipids in NK cells decreased their anti-tumor activity by inhibiting cytotoxic machinery trafficking. In B-cell lymphomas, rich fatty acids in the TME impaired IFNγ secretion by NK cells. The formation of immunological synapses is critical for recognizing and killing cancer cells by NK cells. In liver cancer, inhibition of sphingomyelin biosynthesis in intratumoral NK cells severely dampened the membrane topology and synapse formation, which reduced NK cell cytotoxicity. Amino acid metabolism also regulates NK cell activity. Several works showed that tryptophan-derived kynurenine catalyzed by indoleamine 2,3-dioxygenase (IDO) inhibited NK cell proliferation and decreased activating receptors, including NKp46 and NKG2D, on the surface of NK cells. IDO could also catalyze tryptophan to kynurenine in cancer cells, decreasing the expression of NKG2D ligands on the surface of cancer cells by ADAM10, and this reduced expression of NKG2D ligands inhibited degranulation and IFNγ release by NK cells.

Therapeutic approaches to overcome NK cell exhaustion

Recombinant cytokine drugs are being developed to boost NK cell activation. IL-2 is a potent stimulator of NK cell and cytotoxic T cell survival and increases their killing activity. Several recombinant IL-2 drugs are currently under investigation or approved for the treatment of various cancers, such as lung, bladder, ovarian, and renal cell cancers. IL-12 is secreted mainly by antigen-presenting cells and enhances the proliferation, survival, and cytotoxicity of NK cells. Recombinant IL-12 is currently being tested in clinical trials for the treatment of head and neck cancer in combination with cetuximab, an EGFR inhibitor. IL-15 has similar functions to IL-2 but does not have the activation-induced cell death effect. An IL-15 superagonist ALT-803 is being used in clinical trials to treat various types of cancers, including non-small-cell lung cancer, head and neck cancer, renal cell cancer, and melanoma.

Immune checkpoint inhibitors have been used to block immunosuppressive signals on NK cells to enhance their anti-tumor activity. Blocking the PD-1/PD-L1 inhibitory axis has become a popular therapeutic strategy. PD-1/PD-L1 immune checkpoint inhibitors have been approved for the clinical treatment of various cancers. Recently, a monoclonal antibody targeting LAG-3 has also been approved by the FDA for the treatment of melanoma. Dozens of monoclonal antibodies targeting other immune checkpoints, such as KIR, TIGIT, TIM-3, and NKG2A, are currently being developed and clinically tested. In addition to immune checkpoint inhibitors, agonistic antibodies are also being developed to activate costimulatory receptors on NK cells to enhance their anti-tumor activity. For example, monoclonal antibodies targeting 4-1BB are being tested in clinical trials for the treatment of lymphoma, melanoma, and non-small-cell lung cancer.

Adoptive transfer of NK cells represents another strategy for cancer treatment. Therapeutic NK cells can be purified from peripheral blood or umbilical cord blood or derived from induced pluripotent stem cells. Some NK cell lines, such as NK-92, can also be used for transfusion. Prior to transfusion, several cytokines such as IL-2, IL-12, IL-15, and IL-21 and feeder cells are used to promote NK cell activation and proliferation. Genetically engineered NK cells such as chimeric antigen receptor (CAR)-NK cells and TCR-NK cells are generated to improve the killing ability and specificity of NK cells. For example, anti-CD19 CAR-NK cells have been used in clinical trials to treat lymphoid tumors. Synthetic biology methods are also being investigated to help NK cells overcome immunosuppressive TME. The development of novel therapies based on NK cells and the combination of existing strategies will contribute greatly to cancer research and treatment.

Author contributions

HJ: Writing – original draft. HY: Writing – original draft. HX: Writing – original draft. KL: Writing – review & editing.

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    Concha-Benavente F Kansy B Moskovitz J Moy J Chandran U Ferris RL. PD-L1 mediates dysfunction in activated PD-1+ NK cells in head and neck cancer patients. Cancer Immunol Res (2018 ) 6(12):1548–60

    Not in our library10.1158/2326-6066.cir-18-0062

  58. 58.

    Stanietsky N Simic H Arapovic J Toporik A Levy O Novik A. The interaction of TIGIT with PVR and PVRL2 inhibits human NK cell cytotoxicity. Proc Natl Acad Sci U.S.A. (2009 ) 106(42):17858–63

    Not in our library10.1073/pnas.0903474106

  59. 59.

    Zhang Q Bi J Zheng X Chen Y Wang H Wu W. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity. Nat Immunol (2018 ) 19(7):723–32

    Not in our library10.1038/s41590-018-0132-0

  60. 60.

    Datar I Sanmamed MF Wang J Henick BS Choi J Badri T. Expression analysis and significance of PD-1, LAG-3, and TIM-3 in human non–small cell lung cancer using spatially resolved and multiparametric single-cell analysis. Clin Cancer Res (2019 ) 25(15):4663–73

    Not in our library10.1158/1078-0432.ccr-18-4142

  61. 61.

    Li X Lu H Gu Y Zhang X Zhang G Shi T. Tim-3 suppresses the killing effect of Vγ9Vδ2 T cells on colon cancer cells by reducing perforin and granzyme B expression. Exp Cell Res (2020 ) 386(1):111719

    Not in our library10.1016/j.yexcr.2019.111719

  62. 62.

    Wang Z Zhu J Gu H Yuan Y Zhang B Zhu D. The clinical significance of abnormal Tim-3 expression on NK cells from patients with gastric cancer. Immunol Invest (2015 ) 44(6):578–89

    Not in our library10.3109/08820139.2015.1052145

  63. 63.

    Zhao L Cheng S Fan L Zhang B Xu S. TIM-3: An update on immunotherapy. Int Immunopharmacol (2021 ) 99:107933

    Not in our library10.1016/j.intimp.2021.107933

  64. 64.

    Komita H Koido S Hayashi K Kan S Ito M Kamata Y. Expression of immune checkpoint molecules of T cell immunoglobulin and mucin protein 3/galectin-9 for NK cell suppression in human gastrointestinal stromal tumors. Oncol Rep (2015 ) 34(4):2099–105

    Not in our library10.3892/or.2015.4149

  65. 65.

    Gleason MK Lenvik TR McCullar V Felices M O'Brien MS Cooley SA. Tim-3 is an inducible human natural killer cell receptor that enhances interferon gamma production in response to galectin-9. Blood (2012 ) 119(13):3064–72

    Not in our library10.1182/blood-2011-06-360321

  66. 66.

    Rahmati A Bigam S Elahi S. Galectin-9 promotes natural killer cells activity via interaction with CD44. Front Immunol (2023 ) 14:1131379

    Not in our library10.3389/fimmu.2023.1131379

  67. 67.

    Zhao N-H Qian Y Wu C-S Wang J-W Fang Y Fan X-P. Diagnostic value of NKG2D promoter methylation in hepatitis B virus-associated hepatocellular carcinoma. biomark Med (2019 ) 13(13):1093–105

    Not in our library10.2217/bmm-2019-0102

  68. 68.

    Crane CA Han SJ Barry JJ Ahn BJ Lanier LL Parsa AT. TGF-β downregulates the activating receptor NKG2D on NK cells and CD8+ T cells in glioma patients. Neuro-Oncol (2010 ) 12(1):7–13

    Not in our library10.1093/neuonc/nop009

  69. 69.

    Dasgupta S Bhattacharya-Chatterjee M O’Malley BW Chatterjee SK. Inhibition of NK cell activity through TGF-β1 by down-regulation of NKG2D in a murine model of head and neck cancer. J Immunol (2005 ) 175(8):5541–50

    Not in our library10.4049/jimmunol.175.8.5541

  70. 70.
    Low NKp30, NKp46 and NKG2D expression and reduced cytotoxic activity on NK cells in cervical cancer and precursor lesions · 2009
    No notice
  71. 71.

    Hilpert J Grosse-Hovest L Grünebach F Buechele C Nuebling T Raum T. Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses. J Immunol (2012 ) 189(3):1360–71

    Not in our library10.4049/jimmunol.1200796

  72. 72.
    The Critical Role of the Tumor Microenvironment in Shaping Natural Killer Cell-Mediated Anti-Tumor Immunity · 2013
    No notice
  73. 73.
    Natural killer group 2D receptor and its ligands in cancer immune escape · 2019
    No notice
  74. 74.

    Wang X Lundgren AD Singh P Goodlett DR Plymate SR Wu JD. An six-amino acid motif in the α3 domain of MICA is the cancer therapeutic target to inhibit shedding. Biochem Biophys Res Commun (2009 ) 387(3):476–81

    Not in our library10.1016/j.bbrc.2009.07.062

  75. 75.

    Pietra G Manzini C Rivara S Vitale M Cantoni C Petretto A. Melanoma cells inhibit natural killer cell function by modulating the expression of activating receptors and cytolytic activity. Cancer Res (2012 ) 72(6):1407–15

    Not in our library10.1158/0008-5472.can-11-2544

  76. 76.

    Holt D Ma X Kundu N Fulton A. Prostaglandin E 2 (PGE 2) suppresses natural killer cell function primarily through the PGE 2 receptor EP4. Cancer Immunol Immunother (2011 ) 60:1577–86

    Not in our library10.1007/s00262-011-1064-9

  77. 77.

    Knudsen NH Manguso RT. Tumor-derived PGE2 gives NK cells a headache. Immunity (2020 ) 53(6):1131–2

    Not in our library10.1016/j.immuni.2020.11.018

  78. 78.

    Lee J-C Lee K-M Kim D-W Heo DS. Elevated TGF-β1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol (2004 ) 172(12):7335–40

    Not in our library10.4049/jimmunol.172.12.7335

  79. 79.
    Human Tumour Immune Evasion via TGF-β Blocks NK Cell Activation but Not Survival Allowing Therapeutic Restoration of Anti-Tumour Activity · 2011
    No notice
  80. 80.

    Hoskin DW Mader JS Furlong SJ Conrad DM Blay J. Inhibition of T cell and natural killer cell function by adenosine and its contribution to immune evasion by tumor cells. Int J Oncol (2008 ) 32(3):527–35

    Not in our library10.3892/ijo.32.3.527

  81. 81.

    Williams BA Manzer A Blay J Hoskin DW. Adenosine acts through a novel extracellular receptor to inhibit granule exocytosis by natural killer cells. Biochem Biophys Res Commun (1997 ) 231(2):264–9

    Not in our library10.1006/bbrc.1997.6077

  82. 82.

    Lokshin A Raskovalova T Huang X Zacharia LC Jackson EK Gorelik E. Adenosine-mediated inhibition of the cytotoxic activity and cytokine production by activated natural killer cells. Cancer Res (2006 ) 66(15):7758–65

    Not in our library10.1158/0008-5472.can-06-0478

  83. 83.

    Berti FCB de Oliveira KB Berti F de Oliveira K. IL-10 in cancer: Just a classical immunosuppressive factor or also an immunostimulating one? AIMS Allergy Immunol (2018 ) 2(2):88–97

    Not in our library10.3934/allergy.2018.2.88

  84. 84.

    Huang S Ullrich SE Bar-Eli M. Regulation of tumor growth and metastasis by interleukin-10: the melanoma experience. J Interferon Cytokine Res (1999 ) 19(7):697–703

    Not in our library10.1089/107999099313532

  85. 85.

    Mocellin S Panelli M Wang E Rossi CR Pilati P Nitti D. IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun (2004 ) 5(8):621–30

    Not in our library10.1038/sj.gene.6364135

  86. 86.
    IL-10 Enhances Human Natural Killer Cell Effector Functions via Metabolic Reprogramming Regulated by mTORC1 Signaling · 2021
    Not checked
  87. 87.

    Okumura G Iguchi-Manaka A Murata R Yamashita-Kanemaru Y Shibuya A Shibuya K. Tumor-derived soluble CD155 inhibits DNAM-1–mediated antitumor activity of natural killer cells. J Exp Med (2020 ) 217(4):e20191290

    Not in our library10.1084/jem.20191290

  88. 88.

    Batista IA Quintas ST Melo SA. The interplay of exosomes and NK cells in cancer biology. Cancers (2021 ) 13(3):473

    Not in our library10.3390/cancers13030473

  89. 89.
    Thermal- and Oxidative Stress Causes Enhanced Release of NKG2D Ligand-Bearing Immunosuppressive Exosomes in Leukemia/Lymphoma T and B Cells · 2011
    No notice
  90. 90.
    Circulating exosomes carrying an immunosuppressive cargo interfere with cellular immunotherapy in acute myeloid leukemia · 2017
    No notice
  91. 91.

    Liu C-G Chen J Goh RMW-J Liu Y-X Wang L Ma Z. The role of tumor-derived extracellular vesicles containing noncoding RNAs in mediating immune cell function and its implications from bench to bedside. Pharmacol Res (2023 ) (191):106756

    Not in our library10.1016/j.phrs.2023.106756

  92. 92.

    Tang Q Yang S He G Zheng H Zhang S Liu J. Tumor-derived exosomes in the cancer immune microenvironment and cancer immunotherapy. Cancer Lett (2022 ) (548):215823

    Not in our library10.1016/j.canlet.2022.215823

  93. 93.

    Azizi E Carr AJ Plitas G Cornish AE Konopacki C Prabhakaran S. Single-cell map of diverse immune phenotypes in the breast tumor microenvironment. Cell (2018 ) 174(5):1293–308

    Not in our library10.1016/j.cell.2018.05.060

  94. 94.

    Ghiringhelli F Ménard C Martin F Zitvogel L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol Rev (2006 ) 214(1):229–38

    Not in our library10.1111/j.1600-065x.2006.00445.x

  95. 95.

    Ghiringhelli F Ménard C Terme M Flament C Taieb J Chaput N. CD4+ CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner. J Exp Med (2005 ) 202(8):1075–85

    Not in our library10.1084/jem.20051511

  96. 96.

    Li H Han Y Guo Q Zhang M Cao X. Cancer-expanded myeloid-derived suppressor cells induce anergy of NK cells through membrane-bound TGF-β1. J Immunol (2009 ) 182(1):240–9

    Not in our library10.4049/jimmunol.182.1.240

  97. 97.

    Goh CC Roggerson KM Lee H-C Golden-Mason L Rosen HR Hahn YS. Hepatitis C virus–induced myeloid-derived suppressor cells suppress NK cell IFN-γ production by altering cellular metabolism via arginase-1. J Immunol (2016 ) 196(5):2283–92

    Not in our library10.4049/jimmunol.1501881

  98. 98.

    Hoechst B Voigtlaender T Ormandy L Gamrekelashvili J Zhao F Wedemeyer H. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology (2009 ) 50(3):799–807

    Not in our library10.1002/hep.23054

  99. 99.

    Stiff A Trikha P Mundy-Bosse B McMichael E Mace TA Benner B. Nitric oxide production by myeloid-derived suppressor cells plays a role in impairing Fc receptor–mediated natural killer cell function. Clin Cancer Res (2018 ) 24(8):1891–904

    Not in our library10.1158/1078-0432.ccr-17-0691

  100. 100.

    Nuñez SY Ziblat A Secchiari F Torres NI Sierra JM Raffo Iraolagoitia XL. Human M2 macrophages limit NK cell effector functions through secretion of TGF-β and engagement of CD85j. J Immunol (2018 ) 200(3):1008–15

    Not in our library10.4049/jimmunol.1700737

  101. 101.

    Krneta T Gillgrass A Poznanski S Chew M Lee AJ Kolb M. M2-polarized and tumor-associated macrophages alter NK cell phenotype and function in a contact-dependent manner. J Leukoc Biol (2017 ) 101(1):285–95

    Not in our library10.1189/jlb.3a1215-552r

  102. 102.

    Noy R Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity (2014 ) 41(1):49–61

    Not in our library10.1016/j.immuni.2014.06.010

  103. 103.

    Sun R Xiong Y Liu H Gao C Su L Weng J. Tumor-associated neutrophils suppress antitumor immunity of NK cells through the PD-L1/PD-1 axis. Transl Oncol (2020 ) 13(10):100825

    Not in our library10.1016/j.tranon.2020.100825

  104. 104.

    Romero AI Thorén FB Brune M Hellstrand K. NKp46 and NKG2D receptor expression in NK cells with CD56dim and CD56bright phenotype: regulation by histamine and reactive oxygen species. Br J Haematol (2006 ) 132(1):91–8

    Not in our library10.1111/j.1365-2141.2005.05842.x

  105. 105.

    Valayer A Brea D Lajoie L Avezard L Combes-Soia L Labas V. Neutrophils can disarm NK cell response through cleavage of NKp46. J Leukoc Biol (2017 ) 101(1):253–9

    Not in our library10.1189/jlb.3ab0316-140rr

  106. 106.
    Tumour stromal cells derived from paediatric malignancies display MSC-like properties and impair NK cell cytotoxicity · 2010
    Not checked
  107. 107.

    Petri RM Hackel A Hahnel K Dumitru CA Bruderek K Flohe SB. Activated tissue-resident mesenchymal stromal cells regulate natural killer cell immune and tissue-regenerative function. Stem Cell Rep (2017 ) 9(3):985–98

    Not in our library10.1016/j.stemcr.2017.06.020

  108. 108.

    O’Brien KL Finlay DK. Immunometabolism and natural killer cell responses. Nat Rev Immunol (2019 ) 19(5):282–90

    Not in our library10.1038/s41577-019-0139-2

  109. 109.

    Yang Y Chen L Zheng B Zhou S. Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy. Oncogene (2023 ) 42(1):1–10

    Not in our library10.1038/s41388-022-02562-w

  110. 110.

    Keating SE Zaiatz-Bittencourt V Loftus RM Keane C Brennan K Finlay DK. Metabolic reprogramming supports IFN-γ production by CD56bright NK cells. J Immunol (2016 ) 196(6):2552–60

    Not in our library10.4049/jimmunol.1501783

  111. 111.

    Cong J Wang X Zheng X Wang D Fu B Sun R. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab (2018 ) 28(2):243–55

    Not in our library10.1016/j.cmet.2018.06.021

  112. 112.

    Assmann N O'Brien KL Donnelly RP Dyck L Zaiatz-Bittencourt V Loftus RM. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol (2017 ) 18(11):1197–206

    Not in our library10.1038/ni.3838

  113. 113.
    Glycolysis and Oxidative Phosphorylation Play Critical Roles in Natural Killer Cell Receptor-Mediated Natural Killer Cell Functions · 2020
    No notice
  114. 114.

    Schilling D Tetzlaff F Konrad S Li W Multhoff G. A hypoxia-induced decrease of either MICA/B or Hsp70 on the membrane of tumor cells mediates immune escape from NK cells. Cell Stress Chaperones (2015 ) 20:139–47

    Not in our library10.1007/s12192-014-0532-5

  115. 115.
    Hypoxia Induced Impairment of NK Cell Cytotoxicity against Multiple Myeloma Can Be Overcome by IL-2 Activation of the NK Cells · 2013
    No notice
  116. 116.

    Balsamo M Manzini C Pietra G Raggi F Blengio F Mingari MC. Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur J Immunol (2013 ) 43(10):2756–64

    Not in our library10.1002/eji.201343448

  117. 117.

    Noman MZ Desantis G Janji B Hasmim M Karray S Dessen P. 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(5):781–90

    Not in our library10.1084/jem.20131916

  118. 118.

    Zheng X Qian Y Fu B Jiao D Jiang Y Chen P. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol (2019 ) 20(12):1656–67

    Not in our library10.1038/s41590-019-0511-1

  119. 119.

    Vander Heiden MG Cantley LC Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (2009 ) 324:1029–33

    Not in our library10.1126/science.1160809

  120. 120.

    Brand A Singer K Koehl GE Kolitzus M Schoenhammer G Thiel A. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab (2016 ) 24(5):657–71

    Not in our library10.1016/j.cmet.2016.08.011

  121. 121.

    Harmon C Robinson MW Hand F Almuaili D Mentor K Houlihan DD. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis. Cancer Immunol Res (2019 ) 7(2):335–46

    Not in our library10.1158/2326-6066.cir-18-0481

  122. 122.

    Michelet X Dyck L Hogan A Loftus RM Duquette D Wei K. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol (2018 ) 19(12):1330–40

    Not in our library10.1038/s41590-018-0251-7

  123. 123.

    Kobayashi T Lam PY Jiang H Bednarska K Gloury R Murigneux V. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood (2020 ) 136(26):3004–17

    Not in our library10.1182/blood.2020005602

  124. 124.

    Zheng X Hou Z Qian Y Zhang Y Cui Q Wang X. Tumors evade immune cytotoxicity by altering the surface topology of NK cells. Nat Immunol (2023 ) 24(5):802–13

    Not in our library10.1038/s41590-023-01462-9

  125. 125.

    Chiesa MD Carlomagno S Frumento G Balsamo M Cantoni C Conte R. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46-and NKG2D-activating receptors and regulates NK-cell function. Blood (2006 ) 108(13):4118–25

    Not in our library10.1182/blood-2006-03-006700

  126. 126.

    Frumento G Rotondo R Tonetti M Damonte G Benatti U Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2, 3-dioxygenase. J Exp Med (2002 ) 196(4):459–68

    Not in our library10.1084/jem.20020121

  127. 127.

    Fang X Guo L Xing Z Shi L Liang H Li A. IDO1 can impair NK cells function against non-small cell lung cancer by downregulation of NKG2D Ligand via ADAM10. Pharmacol Res (2022 ) 177:106132

    Not in our library10.1016/j.phrs.2022.106132

  128. 128.

    Gladkov O Ramlau R Serwatowski P Milanowski J Tomeczko J Komarnitsky PB. Cyclophosphamide and tucotuzumab (huKS-IL2) following first-line chemotherapy in responding patients with extensive-disease small-cell lung cancer. Anti-Cancer Drugs (2015 ) 26(10):1061–8

    Not in our library10.1097/cad.0000000000000281

  129. 129.

    Gustavson L Nadeau R Oldfield N. Pharmacokinetics of teceleukin (recombinant human interleukin-2) after intravenous or subcutaneous administration to patients with cancer. J Biol Resp Modif (1989 ) 8(4):440–9.

    Not in our library

  130. 130.

    Majidpoor J Mortezaee K. Interleukin-2 therapy of cancer-clinical perspectives. Int Immunopharmacol (2021 ) 98:107836

    Not in our library10.1016/j.intimp.2021.107836

  131. 131.

    McDermott DF Cheng S-C Signoretti S Margolin KA Clark JI Sosman JA. The high-dose aldesleukin “select” trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res (2015 ) 21(3):561–8

    Not in our library10.1158/1078-0432.ccr-14-1520

  132. 132.

    Luedke E Jaime-Ramirez AC Bhave N Roda J Choudhary MM Kumar B. Cetuximab therapy in head and neck cancer: Immune modulation with interleukin-12 and other natural killer cell–activating cytokines. Surgery (2012 ) 152(3):431–40

    Not in our library10.1016/j.surg.2012.05.035

  133. 133.

    McMichael EL Benner B Atwal LS Courtney NB Mo X Davis ME. A phase I/II trial of cetuximab in combination with interleukin-12 administered to patients with unresectable primary or recurrent head and neck squamous cell carcinoma. Clin Cancer Res (2019 ) 25(16):4955–65

    Not in our library10.1158/1078-0432.ccr-18-2108

  134. 134.
    IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice · 2000
    Not checked
  135. 135.

    Margolin K Morishima C Velcheti V Miller JS Lee SM Silk AW. Phase I trial of ALT-803, a novel recombinant IL15 complex, in patients with advanced solid tumors. Clin Cancer Res (2018 ) 24(22):5552–61

    Not in our library10.1158/1078-0432.ccr-18-0945

  136. 136.

    Wrangle JM Velcheti V Patel MR Garrett-Mayer E Hill EG Ravenel JG. ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. Lancet Oncol (2018 ) 19(5):694–704

    Not in our library10.1016/s1470-2045(18)30148-7

  137. 137.

    Hsu J Hodgins JJ Marathe M Nicolai CJ Bourgeois-Daigneault M-C Trevino TN. Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade. J Clin Investig (2018 ) 128(10):4654–68

    Not in our library10.1172/jci99317

  138. 138.
    The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy · 2020
    No notice
  139. 139.

    Wang D Bauersachs J Berliner D. Immune checkpoint inhibitor associated myocarditis and cardiomyopathy: a translational review. Biology (2023 ) 12(3):472

    Not in our library10.3390/biology12030472

  140. 140.

    Albrecht LJ Livingstone E Zimmer L SChadendorf D. The latest option: nivolumab and relatlimab in advanced melanoma. Curr Oncol Rep (2023 ) 25(6):647–57

    Not in our library10.1007/s11912-023-01406-4

  141. 141.

    Buckle I Guillerey C. Inhibitory receptors and immune checkpoints regulating natural killer cell responses to cancer. Cancers (2021 ) 13(17):4263

    Not in our library10.3390/cancers13174263

  142. 142.

    Alturki NA. Review of the immune checkpoint inhibitors in the context of cancer treatment. J Clin Med (2023 ) 12(13):4301

    Not in our library10.3390/jcm12134301

  143. 143.

    Kohrt HE Thielens A Marabelle A Sagiv-Barfi I Sola C Chanuc F. Anti-KIR antibody enhancement of anti-lymphoma activity of natural killer cells as monotherapy and in combination with anti-CD20 antibodies. Blood (2014 ) 123(5):678–86

    Not in our library10.1182/blood-2013-08-519199

  144. 144.
    Utomilumab in Patients With Immune Checkpoint Inhibitor-Refractory Melanoma and Non-Small-Cell Lung Cancer · 2022
    Not checked
  145. 145.

    Timmerman J Herbaux C Ribrag V Zelenetz AD Houot R Neelapu SS. Urelumab alone or in combination with rituximab in patients with relapsed or refractory B-cell lymphoma. Am J Hematol (2020 ) 95(5):510–20

    Not in our library10.1002/ajh.25757

  146. 146.

    Motallebnejad P Kantardjieff A Cichocki F Azarin SM Hu W-S. Process engineering of natural killer cell-based immunotherapy. Trends Biotechnol (2023 ) 41(10):1314–26

    Not in our library10.1016/j.tibtech.2023.03.018

  147. 147.

    Shin MH Kim J Lim SA Kim J Kim S-J Lee K-M. NK cell-based immunotherapies in cancer. Immune Netw (2020 ) 20(2)

    Not in our library10.4110/in.2020.20.e14

  148. 148.

    Guillerey C Huntington ND Smyth MJ. Targeting natural killer cells in cancer immunotherapy. Nat Immunol (2016 ) 17(9):1025–36

    Not in our library10.1038/ni.3518

  149. 149.

    Pérez-Martínez A Fernández L Valentín J Martínez-Romera I Corral MD Ramírez M. A phase I/II trial of interleukin-15–stimulated natural killer cell infusion after haplo-identical stem cell transplantation for pediatric refractory solid tumors. Cytotherapy (2015 ) 17(11):1594–603

    Not in our library10.1016/j.jcyt.2015.07.011

  150. 150.

    Karahan ZS Aras M Sütlü T. TCR-NK cells: a novel source for adoptive immunotherapy of cancer. Turk J Hematol (2023 ) 40(1):1

    Not in our library10.4274/tjh.galenos.2022.2022.0534

  151. 151.

    Poon AYC Sugimura R. The prospect of genetically engineering natural killer cells for cancer immunotherapy. Biol Open (2022 ) 11(12):bio059396

    Not in our library10.1242/bio.059396

  152. 152.

    Liu E Marin D Banerjee P Macapinlac HA Thompson P Basar R. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med (2020 ) 382(6):545–53

    Not in our library10.1056/nejmoa1910607

  153. 153.

    Clubb JD Gao TA Chen YY. Synthetic biology in the engineering of CAR-T and CAR-NK cell therapies: facts and hopes. Clin Cancer Res (2023 ) 29(8):1390–402

    Not in our library10.1158/1078-0432.ccr-22-1491

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