Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy

Oncogene volume 42, pages 1–10 (2023)Cite this article

Subjects

Abstract

Natural killer (NK) cells belong to the early responder group against cancerous cells and viral infection. Emerging evidence reveals that distinct metabolic reprogramming occurs concurrently with activation and memory formation of NK cells. However, metabolism of NK cells is disturbed in the tumor immune microenvironment, which may promote tumor progression while limiting immunotherapy responses. In this review, we highlight how cell metabolism influences NK cell activity, the key molecular regulators of NK cell metabolism, and emerging strategies to alter metabolism to improve cytotoxicity of NK cells to kill tumor cells for cancer patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Metabolic alterations in activated NK cells.
Fig. 2: Crosstalk between metabolic regulators in NK cells.
Fig. 3: CAR-NK cell therapy and metabolic manipulation.

Similar content being viewed by others

References

  1. Cong J. Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells. Front Immunol. 2020;11:1989.

    Article  CAS  Google Scholar 

  2. Marcais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, et al. The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol. 2014;15:749–57.

    Article  CAS  Google Scholar 

  3. Schafer JR, Salzillo TC, Chakravarti N, Kararoudi MN, Trikha P, Foltz JA, et al. Education-dependent activation of glycolysis promotes the cytolytic potency of licensed human natural killer cells. J Allergy Clin Immunol. 2019;143:346–358. e346.

    Article  CAS  Google Scholar 

  4. Zaiatz-Bittencourt V, Finlay DK, Gardiner CM. Canonical TGF-β Signaling Pathway Represses Human NK Cell Metabolism. J Immunol. 2018;200:3934–41.

    Article  CAS  Google Scholar 

  5. Assmann N, O’Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, et al. Srebp-controlled glucose metabolism is essential for NK cell functional responses. Nat Immunol. 2017;18:1197–206.

    Article  CAS  Google Scholar 

  6. Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, Finlay DK, et al. Metabolic Reprogramming Supports IFN-gamma Production by CD56bright NK Cells. J Immunol. 2016;196:2552–60.

    Article  CAS  Google Scholar 

  7. Cozar B, Greppi M, Carpentier S, Narni-Mancinelli E, Chiossone L, Vivier E. Tumor-Infiltrating Natural Killer Cells. Cancer Disco. 2021;11:34–44.

    Article  CAS  Google Scholar 

  8. Myers JA, Miller JS. Exploring the NK cell platform for cancer immunotherapy. Nat Rev Clin Oncol. 2021;18:85–100.

    Article  Google Scholar 

  9. Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, Gardiner CM, et al. mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol. 2014;193:4477–84.

    Article  CAS  Google Scholar 

  10. Keppel MP, Saucier N, Mah AY, Vogel TP, Cooper MA. Activation-specific metabolic requirements for NK Cell IFN-gamma production. J Immunol. 2015;194:1954–62.

    Article  CAS  Google Scholar 

  11. Romee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, et al. Cytokine activation induces human memory-like NK cells. Blood 2012;120:4751–60.

    Article  CAS  Google Scholar 

  12. Romee R, Rosario M, Berrien-Elliott MM, Wagner JA, Jewell BA, Schappe T, et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci Transl Med. 2016;8:357ra123.

    Article  Google Scholar 

  13. Sun JC, Beilke JN, Lanier LL. Adaptive immune features of natural killer cells. Nature 2009;457:557–61.

    Article  CAS  Google Scholar 

  14. O’Sullivan TE, Johnson LR, Kang HH, Sun JC. BNIP3- and BNIP3L-Mediated Mitophagy Promotes the Generation of Natural Killer Cell Memory. Immunity 2015;43:331–42.

    Article  Google Scholar 

  15. Green DR, Galluzzi L, Kroemer G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 2011;333:1109–12.

    Article  CAS  Google Scholar 

  16. Nandagopal N, Ali AK, Komal AK, Lee SH. The Critical Role of IL-15-PI3K-mTOR Pathway in Natural Killer Cell Effector Functions. Front Immunol. 2014;5:187.

    Article  Google Scholar 

  17. Cichocki F, Wu CY, Zhang B, Felices M, Tesi B, Tuininga K, et al. ARID5B regulates metabolic programming in human adaptive NK cells. J Exp Med. 2018;215:2379–95.

    Article  CAS  Google Scholar 

  18. Lee JH, Phelan P, Shin M, Oh BC, Han X, Im SS, et al. SREBP-1a-stimulated lipid synthesis is required for macrophage phagocytosis downstream of TLR4-directed mTORC1. Proc Natl Acad Sci USA. 2018;115:E12228–E12234.

    Article  CAS  Google Scholar 

  19. Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol. 2013;14:489–99.

    Article  CAS  Google Scholar 

  20. Shao W, Espenshade PJ. Expanding roles for SREBP in metabolism. Cell Metab. 2012;16:414–9.

    Article  CAS  Google Scholar 

  21. Sato R, Okamoto A, Inoue J, Miyamoto W, Sakai Y, Emoto N, et al. Transcriptional regulation of the ATP citrate-lyase gene by sterol regulatory element-binding proteins. J Biol Chem. 2000;275:12497–502.

    Article  CAS  Google Scholar 

  22. Loftus RM, Assmann N, Kedia-Mehta N, O’Brien KL, Garcia A, Gillespie C, et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat Commun. 2018;9:2341.

    Article  Google Scholar 

  23. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011;35:871–82.

    Article  CAS  Google Scholar 

  24. Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, 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;10:872–87.

    Article  CAS  Google Scholar 

  25. Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019;366:1013–21.

    Article  CAS  Google Scholar 

  26. Cichocki F, Valamehr B, Bjordahl R, Zhang B, Rezner B, Rogers P, et al. GSK3 Inhibition Drives Maturation of NK Cells and Enhances Their Antitumor Activity. Cancer Res. 2017;77:5664–75.

    Article  CAS  Google Scholar 

  27. Parameswaran R, Ramakrishnan P, Moreton SA, Xia Z, Hou Y, Lee DA, et al. Repression of GSK3 restores NK cell cytotoxicity in AML patients. Nat Commun. 2016;7:11154.

    Article  CAS  Google Scholar 

  28. Littwitz-Salomon E, Moreira D, Frost JN, Choi C, Liou KT, Ahern DK, et al. Metabolic requirements of NK cells during the acute response against retroviral infection. Nat Commun. 2021;12:5376.

    Article  CAS  Google Scholar 

  29. Dong H, Adams NM, Xu Y, Cao J, Allan DSJ, Carlyle JR, et al. The IRE1 endoplasmic reticulum stress sensor activates natural killer cell immunity in part by regulating c-Myc. Nat Immunol. 2019;20:865–78.

    Article  CAS  Google Scholar 

  30. Huang S, Xing Y, Liu Y. Emerging roles for the ER stress sensor IRE1α in metabolic regulation and disease. J Biol Chem. 2019;294:18726–41.

    Article  CAS  Google Scholar 

  31. Choi C, Finlay DK, Optimising NK. cell metabolism to increase the efficacy of cancer immunotherapy. Stem Cell Res Ther. 2021;12:320.

    Article  CAS  Google Scholar 

  32. Lyssiotis CA, Kimmelman AC. Metabolic Interactions in the Tumor Microenvironment. Trends Cell Biol. 2017;27:863–75.

    Article  CAS  Google Scholar 

  33. Poznanski SM, Singh K, Ritchie TM, Aguiar JA, Fan IY, Portillo AL, et al. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment. Cell Metab. 2021;33:1205–1220.e1205.

    Article  CAS  Google Scholar 

  34. Lian X, Yang K, Li R, Li M, Zuo J, Zheng B, et al. Immunometabolic rewiring in tumorigenesis and anti-tumor immunotherapy. Mol Cancer. 2022;21:27.

    Article  Google Scholar 

  35. Mossmann D, Park S, Hall MN. mTOR signalling and cellular metabolism are mutual determinants in cancer. Nat Rev Cancer. 2018;18:744–57.

    Article  CAS  Google Scholar 

  36. Viel S, Marçais A, Guimaraes FS-F, Loftus R, Rabilloud J, Grau M, et al. TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal. 2016;9:ra19.

    Article  Google Scholar 

  37. Davis MR, Zhu Z, Hansen DM, Bai Q, Fang Y. The role of IL-21 in immunity and cancer. Cancer Lett. 2015;358:107–14.

    Article  CAS  Google Scholar 

  38. Lee DA. Cellular therapy: Adoptive immunotherapy with expanded natural killer cells. Immunol Rev. 2019;290:85–99.

    Article  CAS  Google Scholar 

  39. Petrella TM, Tozer R, Belanger K, Savage KJ, Wong R, Smylie M, et al. Interleukin-21 has activity in patients with metastatic melanoma: a phase II study. J Clin Oncol. 2012;30:3396–401.

    Article  CAS  Google Scholar 

  40. Thompson JA, Curti BD, Redman BG, Bhatia S, Weber JS, Agarwala SS, et al. Phase I study of recombinant interleukin-21 in patients with metastatic melanoma and renal cell carcinoma. J Clin Oncol. 2008;26:2034–9.

    Article  CAS  Google Scholar 

  41. Terren I, Orrantia A, Vitalle J, Zenarruzabeitia O, Borrego FNK. Cell Metabolism and Tumor Microenvironment. Front Immunol. 2019;10:2278.

    Article  CAS  Google Scholar 

  42. Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, et al. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18:157.

    Article  Google Scholar 

  43. Tang YA, Chen YF, Bao Y, Mahara S, Yatim S, Oguz G, et al. Hypoxic tumor microenvironment activates GLI2 via HIF-1α and TGF-β2 to promote chemoresistance in colorectal cancer. Proc Natl Acad Sci USA. 2018;115:E5990–E5999.

    Article  CAS  Google Scholar 

  44. Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat Immunol. 2021;22:205–15.

    Article  CAS  Google Scholar 

  45. Ni J, Wang X, Stojanovic A, Zhang Q, Wincher M, Buhler L, et al. Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity. Immunity 2020;52:1075–1087.e1078.

    Article  CAS  Google Scholar 

  46. Kim J, Shao Y, Kim SY, Kim S, Song HK, Jeon JH, et al. Hypoxia-induced IL-18 increases hypoxia-inducible factor-1alpha expression through a Rac1-dependent NF-kappaB pathway. Mol Biol Cell. 2008;19:433–44.

    Article  CAS  Google Scholar 

  47. Becker-Hapak MK, Shrestha N, McClain E, Dee MJ, Chaturvedi P, Leclerc GM, et al. A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy. Cancer Immunol Res. 2021;9:1071–87.

    Article  CAS  Google Scholar 

  48. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, et al. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016;24:657–71.

    Article  CAS  Google Scholar 

  49. Harmon C, Robinson MW, Hand F, Almuaili D, Mentor K, Houlihan DD, et al. Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis. Cancer Immunol Res. 2019;7:335–46.

    Article  CAS  Google Scholar 

  50. Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ. Imatinib (STI571)-Mediated Changes in Glucose Metabolism in Human Leukemia BCR-ABL-Positive Cells. Clin Cancer Res. 2004;10:6661–8.

    Article  CAS  Google Scholar 

  51. Yin Z, Bai L, Li W, Zeng T, Tian H, Cui J. Targeting T cell metabolism in the tumor microenvironment: an anti-cancer therapeutic strategy. J Exp Clin Cancer Res. 2019;38:403.

    Article  Google Scholar 

  52. Ohta A. A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment. Front Immunol. 2016;7:109.

    Article  Google Scholar 

  53. Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets. Immunol Rev. 2017;276:121–44.

    Article  CAS  Google Scholar 

  54. Morello S, Capone M, Sorrentino C, Giannarelli D, Madonna G, Mallardo D, et al. Soluble CD73 as biomarker in patients with metastatic melanoma patients treated with nivolumab. J Transl Med. 2017;15:244.

    Article  CAS  Google Scholar 

  55. Turiello R, Capone M, Giannarelli D, Morretta E, Monti MC, Madonna G, et al. Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy. J Immunother Cancer. 2020;8:e001689.

    Article  Google Scholar 

  56. He X, Gu Y, Cao Y, Hu B, Fang H, Fei Y, et al. Impact of intratumoural CD73 expression on prognosis and therapeutic response in patients with gastric cancer. Eur J Cancer. 2021;157:114–23.

    Article  CAS  Google Scholar 

  57. 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;66:7758–65.

    Article  CAS  Google Scholar 

  58. Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS, Messaoudene M, et al. A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment. Cancer Res. 2018;78:1003–16.

    Article  CAS  Google Scholar 

  59. Chiappori A, Williams CC, Creelan BC, Tanvetyanon T, Gray JE, Haura EB, et al. Phase I/II study of the A2AR antagonist NIR178 (PBF-509), an oral immunotherapy, in patients (pts) with advanced NSCLC. J Clin Oncol. 2018;36:9089–9089. 15_suppl

    Article  Google Scholar 

  60. Chiappori AA, Creelan B, Tanvetyanon T, Gray JE, Haura EB, Thapa R, et al. Phase I Study of Taminadenant (PBF509/NIR178), an Adenosine 2 A Receptor Antagonist, with or without Spartalizumab (PDR001), in Patients with Advanced Non-Small Cell Lung Cancer. Clin Cancer Res. 2022;28:2313–20.

    Article  CAS  Google Scholar 

  61. Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, et al. A2AR Antagonism with CPI-444 Induces Antitumor Responses and Augments Efficacy to Anti-PD-(L)1 and Anti-CTLA-4 in Preclinical Models. Cancer Immunol Res. 2018;6:1136–49.

    Article  CAS  Google Scholar 

  62. Ghaben AL, Scherer PE. Adipogenesis and metabolic health. Nat Rev Mol Cell Biol. 2019;20:242–58.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  64. Wang J, Li Y. CD36 tango in cancer: signaling pathways and functions. Theranostics 2019;9:4893–908.

    Article  CAS  Google Scholar 

  65. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E, et al. CD36-mediated ferroptosis dampens intratumoral CD8( + ) T cell effector function and impairs their antitumor ability. Cell Metab. 2021;33:1001–1012.e1005.

    Article  CAS  Google Scholar 

  66. Montaigne D, Butruille L, Staels B. PPAR control of metabolism and cardiovascular functions. Nat Rev Cardiol. 2021;18:809–23.

    Article  CAS  Google Scholar 

  67. Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol. 2020;21:298–308.

    Article  Google Scholar 

  68. Yao CH, Liu GY, Wang R, Moon SH, Gross RW, Patti GJ. Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of beta-oxidation. PLoS Biol. 2018;16:e2003782.

    Article  Google Scholar 

  69. Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R, Ma EH, et al. Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation. Cell Metab. 2018;28:504–515.e507.

    Article  CAS  Google Scholar 

  70. O’Connor RS, Guo L, Ghassemi S, Snyder NW, Worth AJ, Weng L, et al. The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep. 2018;8:6289.

    Article  Google Scholar 

  71. Zheng X, Qian Y, Fu B, Jiao D, Jiang Y, Chen P, et al. Mitochondrial fragmentation limits NK cell-based tumor immunosurveillance. Nat Immunol. 2019;20:1656–67.

    Article  CAS  Google Scholar 

  72. Slattery K, Gardiner CM. NK Cell Metabolism and TGFβ - Implications for Immunotherapy. Front Immunol. 2019;10:2915.

    Article  CAS  Google Scholar 

  73. Shi M, Zhu J, Wang R, Chen X, Mi L, Walz T, et al. Latent TGF-β structure and activation. Nature 2011;474:343–9.

    Article  CAS  Google Scholar 

  74. Slattery K, Woods E, Zaiatz-Bittencourt V, Marks S, Chew S, Conroy M, et al. TGFβ drives NK cell metabolic dysfunction in human metastatic breast cancer. J Immunother Cancer. 2021;9:e002044.

    Article  Google Scholar 

  75. Zhao Y, Hu J, Li R, Song J, Kang Y, Liu S, et al. Enhanced NK cell adoptive antitumor effects against breast cancer in vitro via blockade of the transforming growth factor-β signaling pathway. Onco Targets Ther. 2015;8:1553–9.

    Google Scholar 

  76. Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, et al. Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells. Nat Immunol. 2017;18:1004–15.

    Article  CAS  Google Scholar 

  77. Shaim H, Shanley M, Basar R, Daher M, Gumin J, Zamler DB, et al. Targeting the αv integrin/TGF-β axis improves natural killer cell function against glioblastoma stem cells. J Clin Invest. 2021;131:e142116.

    Article  CAS  Google Scholar 

  78. Lind H, Gameiro SR, Jochems C, Donahue RN, Strauss J, Gulley JM, et al. Dual targeting of TGF-β and PD-L1 via a bifunctional anti-PD-L1/TGF-βRII agent: status of preclinical and clinical advances. J Immunother Cancer. 2020;8:e000433.

    Article  Google Scholar 

  79. Strauss J, Gatti-Mays ME, Cho BC, Hill A, Salas S, McClay E, et al. Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in patients with human papillomavirus-associated malignancies. J Immunother Cancer. 2020;8:e001395.

    Article  Google Scholar 

  80. Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFbeta, in Advanced Solid Tumors. Clin Cancer Res. 2018;24:1287–95.

    Article  CAS  Google Scholar 

  81. Paz-Ares L, Kim TM, Vicente D, Felip E, Lee DH, Lee KH, et al. Bintrafusp Alfa, a Bifunctional Fusion Protein Targeting TGF-beta and PD-L1, in Second-Line Treatment of Patients With NSCLC: Results From an Expansion Cohort of a Phase 1 Trial. J Thorac Oncol. 2020;15:1210–22.

    Article  CAS  Google Scholar 

  82. Cong J, Wang X, Zheng X, Wang D, Fu B, Sun R, et al. Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression. Cell Metab. 2018;28:243–255.e245.

    Article  CAS  Google Scholar 

  83. Li F, Huangyang P, Burrows M, Guo K, Riscal R, Godfrey J, et al. FBP1 loss disrupts liver metabolism and promotes tumorigenesis through a hepatic stellate cell senescence secretome. Nat Cell Biol. 2020;22:728–39.

    Article  Google Scholar 

  84. Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S, et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell. 2013;23:316–31.

    Article  CAS  Google Scholar 

  85. Rossi J, Paczkowski P, Shen YW, Morse K, Flynn B, Kaiser A, et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 2018;132:804–14.

    Article  CAS  Google Scholar 

  86. Chou CK, Turtle CJ. Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy. Bone Marrow Transpl. 2019;54:780–4. Suppl 2

    Article  Google Scholar 

  87. Shah NN, Fry TJ. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol. 2019;16:372–85.

    CAS  Google Scholar 

  88. Saetersmoen ML, Hammer Q, Valamehr B, Kaufman DS, Malmberg KJ. Off-the-shelf cell therapy with induced pluripotent stem cell-derived natural killer cells. Semin Immunopathol. 2019;41:59–68.

    Article  Google Scholar 

  89. Zheng L, Ren L, Kouhi A, Khawli LA, Hu P, Kaslow HR, et al. A Humanized Lym-1 CAR with Novel DAP10/DAP12 Signaling Domains Demonstrates Reduced Tonic Signaling and Increased Antitumor Activity in B-Cell Lymphoma Models. Clin Cancer Res. 2020;26:3694–706.

    Article  CAS  Google Scholar 

  90. Christodoulou I, Ho WJ, Marple A, Ravich JW, Tam A, Rahnama R, et al. Engineering CAR-NK cells to secrete IL-15 sustains their anti-AML functionality but is associated with systemic toxicities. J Immunother Cancer. 2021;9:e003894.

    Article  Google Scholar 

  91. Tarannum M, Romee R. Cytokine-induced memory-like natural killer cells for cancer immunotherapy. Stem Cell Res Ther. 2021;12:592.

    Article  CAS  Google Scholar 

  92. Chini CCS, Peclat TR, Warner GM, Kashyap S, Espindola-Netto JM, de Oliveira GC, et al. CD38 ecto-enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels. Nat Metab. 2020;2:1284–304.

    Article  CAS  Google Scholar 

  93. Feske S. Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol. 2007;7:690–702.

    Article  CAS  Google Scholar 

  94. Chatterjee S, Daenthanasanmak A, Chakraborty P, Wyatt MW, Dhar P, Selvam SP, et al. CD38-NAD(+) Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab. 2018;27:85–100.e108.

    Article  CAS  Google Scholar 

  95. Woan KV, Kim H, Bjordahl R, Davis ZB, Gaidarova S, Goulding J, et al. Harnessing features of adaptive NK cells to generate iPSC-derived NK cells for enhanced immunotherapy. Cell Stem Cell. 2021;28:2062–2075.e2065.

    Article  CAS  Google Scholar 

  96. Cho H, Kim KH, Lee H, Kim CG, Chung H, Choi YS, et al. Adaptive Natural Killer Cells Facilitate Effector Functions of Daratumumab in Multiple Myeloma. Clin Cancer Res. 2021;27:2947–58.

    Article  CAS  Google Scholar 

  97. Felices M, Lenvik AJ, McElmurry R, Chu S, Hinderlie P, Bendzick L, et al. Continuous treatment with IL-15 exhausts human NK cells via a metabolic defect. JCI Insight. 2018;3:e96219.

    Article  Google Scholar 

  98. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors. N Engl J Med. 2020;382:545–53.

    Article  CAS  Google Scholar 

  99. Liu E, Tong Y, Dotti G, Shaim H, Savoldo B, Mukherjee M, et al. Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity. Leukemia 2018;32:520–31.

    Article  CAS  Google Scholar 

  100. Daher M, Basar R, Gokdemir E, Baran N, Uprety N, Nunez Cortes AK, et al. Targeting a cytokine checkpoint enhances the fitness of armored cord blood CAR-NK cells. Blood 2021;137:624–36.

    Article  CAS  Google Scholar 

  101. Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, et al. CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol. 2016;17:816–24.

    Article  CAS  Google Scholar 

  102. Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H. Negative Regulation of Cytokine Signaling in Immunity. Cold Spring Harb Perspect Biol. 2018;10:a028571.

    Article  Google Scholar 

  103. Putz EM, Guillerey C, Kos K, Stannard K, Miles K, Delconte RB, et al. Targeting cytokine signaling checkpoint CIS activates NK cells to protect from tumor initiation and metastasis. Oncoimmunology 2017;6:e1267892.

    Article  Google Scholar 

  104. Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, et al. Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity. Cell Stem Cell. 2020;27:224–237.e226.

    Article  CAS  Google Scholar 

  105. Pan R, Ryan J, Pan D, Wucherpfennig KW, Letai A. Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis. Cell 2022;185:1521–1538.e1518.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (grant #82273255, #81822034, #81821002, and #81773119 to SZ), National Key Research and Development Program of China (grant #2022YFA1106600, #2017YFA0106800 and #2018YFA0109200 to SZ), Sichuan Science-Technology Project (grant #22ZYZYTS0070 and #2019YFH0144 to SZ), Direct Scientific Research Grants from West China Second Hospital, Sichuan University (grant #KS021 and #K1907 to SZ).

Author information

Author notes

  1. These authors contributed equally: Yuqing Yang, Lin Chen, Bohao Zheng.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE and State Key Laboratory of Biotherapy, West China Second Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, P. R. China

    Yuqing Yang, Lin Chen & Shengtao Zhou

  2. Wuxi School of Medicine, Jiangnan University, Wuxi, P. R. China

    Bohao Zheng

Authors
  1. Yuqing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bohao Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shengtao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

STZ conceived and designed this review. YQY, LC, and BHZ wrote the paper and draw the figures. YQY and STZ revised the paper.

Corresponding author

Correspondence to Shengtao Zhou.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, Y., Chen, L., Zheng, B. et al. Metabolic hallmarks of natural killer cells in the tumor microenvironment and implications in cancer immunotherapy. Oncogene 42, 1–10 (2023). https://doi.org/10.1038/s41388-022-02562-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02562-w

This article is cited by

Search

Advanced search

Quick links