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Abstract

With the significant successes of immune checkpoint blockade and adoptive cellular therapy, immunotherapy has now become an established treatment option to effectively treat cancer. However, the full potential of this treatment modality has yet to be realized, as there are many additional mechanisms whereby tumors continue to evade immune destruction. To this end, metabolic reprogramming by cancer cells serves not only to promote their own growth but also to create an immunosuppressive tumor microenvironment. The tumor metabolic microenvironment not only inhibits antitumor effector function but also supports the differentiation and function of suppressive immune cells. In this review, we delineate the major metabolic programs of cancer cells and immune cells. Furthermore, we discuss the role of so-called metabolic checkpoints that promote immune evasion and tumor growth. Finally, we review current and potential future strategies to target metabolism in order to not simply inhibit tumor growth but also enhance antitumor immune responses. Such strategies have the great potential to enhance the breadth and depth of immunotherapy for cancer by targeting metabolic checkpoints.

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2023-04-11
2024-04-18
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Literature Cited

  1. Adams WC, Chen YH, Kratchmarov R, Yen B, Nish SA et al. 2016. Anabolism-associated mitochondrial stasis driving lymphocyte differentiation over self-renewal. Cell Rep 17:3142–52
    [Google Scholar]
  2. Al-Khami AA, Zheng L, Del Valle L, Hossain F, Wyczechowska D et al. 2017. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells. OncoImmunology 6:e1344804
    [Google Scholar]
  3. Allard B, Longhi MS, Robson SC, Stagg J. 2017. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol. Rev. 276:121–44
    [Google Scholar]
  4. Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L et al. 2017. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:1282–93.e7
    [Google Scholar]
  5. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA et al. 2009. mTOR regulates memory CD8 T-cell differentiation. Nature 460:108–12
    [Google Scholar]
  6. Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S et al. 2020. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585:277–82
    [Google Scholar]
  7. Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G et al. 2016. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24:5657–71
    [Google Scholar]
  8. Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang C-H et al. 2016. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 186:163–76
    [Google Scholar]
  9. Cascone T, McKenzie JA, Mbofung RM, Punt S, Wang Z et al. 2018. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab 27:977–87.e4
    [Google Scholar]
  10. Cham CM, Driessens G, O'Keefe JP, Gajewski TF 2008. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur. J. Immunol. 38:2438–50
    [Google Scholar]
  11. Chang C-H, Curtis JD, Maggi LB, Faubert B, Villarino AV et al. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239–51
    [Google Scholar]
  12. Chang C-H, Qiu J, O'Sullivan D, Buck MD, Noguchi T et al. 2015. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–41
    [Google Scholar]
  13. Chapman NM, Chi H 2022. Metabolic adaptation of lymphocytes in immunity and disease. Immunity 55:14–30
    [Google Scholar]
  14. Chisolm DA, Savic D, Moore AJ, Ballesteros-Tato A, León B et al. 2017. CCCTC-binding factor translates interleukin 2- and α-ketoglutarate-sensitive metabolic changes in T cells into context-dependent gene programs. Immunity 47:2251–67.e7
    [Google Scholar]
  15. Chisolm DA, Weinmann AS. 2018. Connections between metabolism and epigenetics in programming cellular differentiation. Annu. Rev. Immunol. 36:221–46
    [Google Scholar]
  16. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL et al. 2012. Hypoxia-inducible factor-1 alpha–dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. PNAS 109:41E2784–93
    [Google Scholar]
  17. Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM et al. 2014. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:559–63
    [Google Scholar]
  18. Corzo CA, Condamine T, Lu L, Cotter MJ, Youn JI et al. 2010. HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment. J. Exp. Med. 207:2439–53
    [Google Scholar]
  19. de la Cruz-Lopez KG, Castro-Munoz LJ, Reyes-Hernandez DO, Garcia-Carranca A, Manzo-Merino J. 2019. Lactate in the regulation of tumor microenvironment and therapeutic approaches. Front. Oncol. 9:1143
    [Google Scholar]
  20. De Palma M, Biziato D, Petrova TV. 2017. Microenvironmental regulation of tumour angiogenesis. Nat. Rev. Cancer 17:457–74
    [Google Scholar]
  21. Deng J, Li J, Sarde A, Lines JL, Lee YC et al. 2019. Hypoxia-induced VISTA promotes the suppressive function of myeloid-derived suppressor cells in the tumor microenvironment. Cancer Immunol. Res. 7:1079–90
    [Google Scholar]
  22. Dudzinski SO, Bader JE, Beckermann KE, Young KL, Hongo R et al. 2021. Leptin augments antitumor immunity in obesity by repolarizing tumor-associated macrophages. J. Immunol. 207:3122–30
    [Google Scholar]
  23. Dyck L, Prendeville H, Raverdeau M, Wilk MM, Loftus RM et al. 2022. Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function. J. Exp. Med. 219:3e20210042
    [Google Scholar]
  24. Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M et al. 2016. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537:539–43
    [Google Scholar]
  25. Facciabene A, Peng X, Hagemann IS, Balint K, Barchetti A et al. 2011. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475:226–30
    [Google Scholar]
  26. Faubert B, Li KY, Cai L, Hensley CT, Kim J et al. 2017. Lactate metabolism in human lung tumors. Cell 171:358–71.e9
    [Google Scholar]
  27. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J et al. 2007. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–19
    [Google Scholar]
  28. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC et al. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–77
    [Google Scholar]
  29. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL et al. 2014. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J. Biol. Chem. 289:7884–96
    [Google Scholar]
  30. Gabrilovich DI. 2017. Myeloid-derived suppressor cells. Cancer Immunol. Res. 5:3–8
    [Google Scholar]
  31. Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y et al. 2016. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167:829–42.e13
    [Google Scholar]
  32. Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ et al. 2016. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17:1459–66
    [Google Scholar]
  33. Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M et al. 2015. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Investig. 125:194–207
    [Google Scholar]
  34. Godin-Ethier J, Hanafi LA, Piccirillo CA, Lapointe R. 2011. Indoleamine 2,3-dioxygenase expression in human cancers: clinical and immunologic perspectives. Clin. Cancer Res. 17:6985–91
    [Google Scholar]
  35. Gropper Y, Feferman T, Shalit T, Salame TM, Porat Z, Shakhar G. 2017. Culturing CTLs under hypoxic conditions enhances their cytolysis and improves their anti-tumor function. Cell Rep 20:2547–55
    [Google Scholar]
  36. Harel M, Ortenberg R, Varanasi SK, Mangalhara KC, Mardamshina M et al. 2019. Proteomics of melanoma response to immunotherapy reveals mitochondrial dependence. Cell 179:236–50.e18
    [Google Scholar]
  37. Henze AT, Mazzone M. 2016. The impact of hypoxia on tumor-associated macrophages. J. Clin. Investig. 126:3672–79
    [Google Scholar]
  38. Ho P-CC, Bihuniak JD, Macintyre AN, Staron M, Liu X et al. 2015. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–28
    [Google Scholar]
  39. Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. 2013. Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. J. Exp. Med. 210:1389–402
    [Google Scholar]
  40. Hou AJ, Chen LC, Chen YY. 2021. Navigating CAR-T cells through the solid-tumour microenvironment. Nat. Rev. Drug. Discov. 20:531–50
    [Google Scholar]
  41. Huang SC, Smith AM, Everts B, Colonna M, Pearce EL et al. 2016. Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45:817–30
    [Google Scholar]
  42. Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:115–18
    [Google Scholar]
  43. Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y et al. 2015. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42:419–30
    [Google Scholar]
  44. Jian SL, Chen WW, Su YC, Su YW, Chuang TH et al. 2017. Glycolysis regulates the expansion of myeloid-derived suppressor cells in tumor-bearing hosts through prevention of ROS-mediated apoptosis. Cell Death Dis. 8:e2779
    [Google Scholar]
  45. Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A et al. 2018. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 175:71780–95.e19
    [Google Scholar]
  46. Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE et al. 2016. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44:380–90
    [Google Scholar]
  47. Klebanoff CA, Crompton JG, Leonardi AJ, Yamamoto TN, Chandran SS et al. 2017. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy. JCI Insight 2:23e95103
    [Google Scholar]
  48. Klein Geltink RI, Edwards-Hicks J, Apostolova P, O'Sullivan D, Sanin DE et al. 2020. Metabolic conditioning of CD8+ effector T cells for adoptive cell therapy. Nat. Metab. 2:703–16
    [Google Scholar]
  49. Klein Geltink RI, O'Sullivan D, Corrado M, Bremser A, Buck MD et al. 2017. Mitochondrial priming by CD28. Cell 171:385–97.e11
    [Google Scholar]
  50. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G et al. 2015. Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8:ra97
    [Google Scholar]
  51. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT et al. 2022. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 40:201–18.e9
    [Google Scholar]
  52. Leone RD, Emens LA. 2018. Targeting adenosine for cancer immunotherapy. J. Immunother. Cancer 6:57
    [Google Scholar]
  53. Leone RD, Powell JD. 2020. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20:516–31
    [Google Scholar]
  54. Leone RD, Zhao L, Englert JM, Sun IM, Oh MH et al. 2019. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366:1013–21
    [Google Scholar]
  55. Li H, Bullock K, Gurjao C, Braun D, Shukla SA et al. 2019. Metabolomic adaptations and correlates of survival to immune checkpoint blockade. Nat. Commun. 10:4346
    [Google Scholar]
  56. Li W, Tanikawa T, Kryczek I, Xia H, Li G et al. 2018. Aerobic glycolysis controls myeloid-derived suppressor cells and tumor immunity via a specific CEBPB isoform in triple-negative breast cancer. Cell Metab 28:87–103.e6
    [Google Scholar]
  57. Liu PS, Wang H, Li X, Chao T, Teav T et al. 2017. α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18:985–94
    [Google Scholar]
  58. Ma EH, Bantug G, Griss T, Condotta S, Johnson RM et al. 2017. Serine is an essential metabolite for effector T cell expansion. Cell Metab 25:345–57
    [Google Scholar]
  59. Ma R, Ji T, Zhang H, Dong W, Chen X et al. 2018. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8+ T cells. Nat. Cell Biol. 20:21–27
    [Google Scholar]
  60. Ma X, Bi E, Lu Y, Su P, Huang C et al. 2019. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab 30:143–56.e5
    [Google Scholar]
  61. Ma X, Xiao L, Liu L, Ye L, Su P et al. 2021. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab 33:1001–12.e5
    [Google Scholar]
  62. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC et al. 2014. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61–72
    [Google Scholar]
  63. Martinez FO, Gordon S 2014. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6:13
    [Google Scholar]
  64. Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C et al. 2018a. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep 22:1509–21
    [Google Scholar]
  65. Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ et al. 2018b. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 215:1091–100
    [Google Scholar]
  66. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. 2010. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185:3190–98
    [Google Scholar]
  67. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ et al. 2011. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186:3299–303
    [Google Scholar]
  68. Mills CD, Shearer J, Evans R, Caldwell MD. 1992. Macrophage arginine metabolism and the inhibition or stimulation of cancer. J. Immunol. 149:2709–14
    [Google Scholar]
  69. Moller SH, Hsueh PC, Yu YR, Zhang L, Ho PC. 2022a. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging. Cell Metab 34:378–95
    [Google Scholar]
  70. Moller SH, Wang L, Ho PC. 2022b. Metabolic programming in dendritic cells tailors immune responses and homeostasis. Cell Mol. Immunol. 19:370–83
    [Google Scholar]
  71. Munn DH, Mellor AL. 2016. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:193–207
    [Google Scholar]
  72. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. 1999. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J. Exp. Med. 189:1363–72
    [Google Scholar]
  73. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Yet al 2005. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 22:5633–42
    [Google Scholar]
  74. Nabe S, Yamada T, Suzuki J, Toriyama K, Yasuoka T et al. 2018. Reinforce the antitumor activity of CD8+ T cells via glutamine restriction. Cancer Sci 109:3737–50
    [Google Scholar]
  75. Najjar YG, Menk AV, Sander C, Rao U, Karunamurthy A et al. 2019. Tumor cell oxidative metabolism as a barrier to PD-1 blockade immunotherapy in melanoma. JCI Insight 4:5e124989
    [Google Scholar]
  76. Nakaya M, Xiao Y, Zhou X, Chang J-HH, Chang M et al. 2014. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692–705
    [Google Scholar]
  77. Nelson DL, Cox MM, Lehninger AL. 2017. Lehninger Principles of Biochemistry New York: W.H. Freeman
  78. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S et al. 2014. PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J. Exp. Med. 211:781–90
    [Google Scholar]
  79. Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y et al. 2008. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112:1822–31
    [Google Scholar]
  80. Oh MH, Sun IH, Zhao L, Leone RD, Sun IM et al. 2020. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Investig. 130:3865–84
    [Google Scholar]
  81. Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D et al. 2006. A2A adenosine receptor protects tumors from antitumor T cells. PNAS 103:13132–37
    [Google Scholar]
  82. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I et al. 2005. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell. Biol. 25:9543–53
    [Google Scholar]
  83. Pastorekova S, Gillies RJ. 2019. The role of carbonic anhydrase IX in cancer development: links to hypoxia, acidosis, and beyond. Cancer Metastasis Rev 38:65–77
    [Google Scholar]
  84. Pathria P, Louis TL, Varner JA. 2019. Targeting tumor-associated macrophages in cancer. Trends Immunol 40:310–27
    [Google Scholar]
  85. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B et al. 2015. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6:6692
    [Google Scholar]
  86. Pavlova NN, Zhu J, Thompson CB. 2022. The hallmarks of cancer metabolism: still emerging. Cell Metab 34:355–77
    [Google Scholar]
  87. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H et al. 2009. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:103–7
    [Google Scholar]
  88. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. 2016. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354:481–84
    [Google Scholar]
  89. Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, Russell S, Weber AM et al. 2016. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res 76:1381–90
    [Google Scholar]
  90. Plitas G, Rudensky AY. 2020. Regulatory T cells in cancer. Annu. Rev. Cancer Biol. 4:459–77
    [Google Scholar]
  91. Powell JD, Patel CH, Sun I-H 2022. Immunometabolism. Paul's Fundamental Immunology MF Flajnik, NJ Singh, SM Holland 161–203. Philadelphia: Wolters Kluwer. , 8th ed..
    [Google Scholar]
  92. Previte DM, Martins CP, O'Connor EC, Marre ML, Coudriet GM et al. 2019. Lymphocyte activation gene-3 maintains mitochondrial and metabolic quiescence in naive CD4+ T cells. Cell Rep 27:129–41.e4
    [Google Scholar]
  93. Qiu J, Villa M, Sanin DE, Buck MD, O'Sullivan D et al. 2019. Acetate promotes T cell effector function during glucose restriction. Cell Rep 27:2063–74.e5
    [Google Scholar]
  94. Ribas A, Wolchok JD. 2018. Cancer immunotherapy using checkpoint blockade. Science 359:1350–55
    [Google Scholar]
  95. Ringel AE, Drijvers JM, Baker GJ, Catozzi A, Garcia-Canaveras JC et al. 2020. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 183:1848–66.e26
    [Google Scholar]
  96. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R et al. 2019. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N. Engl. J. Med. 380:1116–27
    [Google Scholar]
  97. Rivadeneira DB, DePeaux K, Wang Y, Kulkarni A, Tabib T et al. 2019. Oncolytic viruses engineered to enforce leptin expression reprogram tumor-infiltrating T cell metabolism and promote tumor clearance. Immunity 51:548–60.e4
    [Google Scholar]
  98. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE et al. 2016. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:374–88
    [Google Scholar]
  99. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. 2017. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol. Res. 5:9–16
    [Google Scholar]
  100. Scharping NE, Rivadeneira DB, Menk AV, Vignali PDA, Ford BR et al. 2021. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22:205–15
    [Google Scholar]
  101. Semenza GL. 2010. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29:625–34
    [Google Scholar]
  102. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. 2017. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168:707–23
    [Google Scholar]
  103. Sinclair LV, Rolf J, Emslie E, Shi Y-BB, Taylor PM, Cantrell DA. 2013. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14:500–8
    [Google Scholar]
  104. Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR et al. 2017. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2:12e93411
    [Google Scholar]
  105. Srivastava MK, Sinha P, Clements VK, Rodriguez P, Ostrand-Rosenberg S. 2010. Myeloid-derived suppressor cells inhibit T-cell activation by depleting cystine and cysteine. Cancer Res 70:68–77
    [Google Scholar]
  106. Steinert EM, Vasan K, Chandel NS. 2021. Mitochondrial metabolism regulation of T cell-mediated immunity. Annu. Rev. Immunol. 39:395–416
    [Google Scholar]
  107. Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG et al. 2013. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J. Clin. Investig. 123:4479–88
    [Google Scholar]
  108. Sullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY et al. 2019. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. eLife 8:e44235
    [Google Scholar]
  109. Tak E, Jung DH, Kim SH, Park GC, Jun DY et al. 2017. Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure. Toxicol. Appl. Pharmacol. 314:72–81
    [Google Scholar]
  110. Tang K, Wu YH, Song Y, Yu B 2021. Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors in clinical trials for cancer immunotherapy. J. Hematol. Oncol. 14:68
    [Google Scholar]
  111. Topalian SL, Drake CG, Pardoll DM. 2015. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27:4450–61
    [Google Scholar]
  112. Triplett TA, Garrison KC, Marshall N, Donkor M, Blazeck J et al. 2018. Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme. Nat. Biotechnol. 36:758–64
    [Google Scholar]
  113. Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT et al. 2016. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540:236–41
    [Google Scholar]
  114. van der Windt G, Everts B, Chang C-H, Curtis JD, Freitas TC et al. 2011. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36:168–78
    [Google Scholar]
  115. van der Windt GJ, O'Sullivan D, Everts B, Huang SC, Buck MD et al. 2013. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. PNAS 110:14336–41
    [Google Scholar]
  116. Vander Heiden MG, Cantley LC, Thompson CB. 2009. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–33
    [Google Scholar]
  117. Vardhana SA, Hwee MA, Berisa M, Wells DK, Yost KE et al. 2020. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21:1022–33
    [Google Scholar]
  118. Walenta S, Wetterling M, Lehrke M, Schwickert G, Sundfor K et al. 2000. High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers. Cancer Res 60:916–21
    [Google Scholar]
  119. Wang H, Franco F, Tsui YC, Xie X, Trefny MP et al. 2020. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21:298–308
    [Google Scholar]
  120. Wang R, Dillon CP, Shi L, Milasta S, Carter R et al. 2011. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–82
    [Google Scholar]
  121. Warburg O, Posener K, Negelein E. 1924. Ueber den Stoffwechsel der Tumoren. Biochem. Z. 152:319–44
    [Google Scholar]
  122. Watson MJ, Vignali PDA, Mullett SJ, Overacre-Delgoffe AE, Peralta RM et al. 2021. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591:645–51
    [Google Scholar]
  123. Weiss JM, Davies LC, Karwan M, Ileva L, Ozaki MK et al. 2018. Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors. J. Clin. Investig. 128:3794–805
    [Google Scholar]
  124. Westendorf AM, Skibbe K, Adamczyk A, Buer J, Geffers R et al. 2017. Hypoxia enhances immunosuppression by inhibiting CD4+ effector T cell function and promoting Treg activity. Cell. Physiol. Biochem. 41:1271–84
    [Google Scholar]
  125. Wu H, Han Y, Rodriguez Sillke Y, Deng H, Siddiqui S et al. 2019. Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol. Med. 11:e10698
    [Google Scholar]
  126. Xu S, Chaudhary O, Rodriguez-Morales P, Sun X, Chen D et al. 2021. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 54:1561–77.e7
    [Google Scholar]
  127. Yang W, Bai Y, Xiong Y, Zhang J, Chen S et al. 2016. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531:651–55
    [Google Scholar]
  128. Yokosuka T, Takamatsu M, Kobayashi-Imanishi W, Hashimoto-Tane A, Azuma M, Saito T. 2012. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209:1201–17
    [Google Scholar]
  129. Yu YR, Imrichova H, Wang H, Chao T, Xiao Z et al. 2020. Disturbed mitochondrial dynamics in CD8+ TILs reinforce T cell exhaustion. Nat. Immunol. 21:1540–51
    [Google Scholar]
  130. Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M et al. 2021. CTLA-4 blockade drives loss of Treg stability in glycolysis-low tumours. Nature 591:652–58
    [Google Scholar]
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