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Annual Review of Cancer Biology

Volume 5, 2021

Immunometabolism in the Tumor Microenvironment

Abstract

Advances in immunotherapy have underscored the importance of antitumor immune responses in controlling cancer. However, the tumor microenvironment (TME) imposes several obstacles to the proper function of immune cells, including a metabolically challenging and immunosuppressive microenvironment. The increased metabolic activity of tumor cells can lead to the depletion of key nutrients required by immune cells and the accumulation of byproducts that hamper antitumor immunity. Furthermore, the presence of suppressive immune cells, such as regulatory T cells and myeloid-derived suppressor cells, and the expression of immune inhibitory receptors can negatively impact immune cell metabolism and function. This review summarizes the metabolic reprogramming that is characteristic of various immune cell subsets, discusses how the metabolism and function of immune cells are shaped by the TME, and highlights how therapeutic interventions aimed at improving the metabolic fitness of immune cells and alleviating the metabolic constraints in the TME can boost antitumor immunity.

Keyword(s): immunology, immunometabolism, immunotherapy, metabolism, T cell exhaustion, tumor microenvironment
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/content/journals/10.1146/annurev-cancerbio-030518-055817
2021-03-04
2025-04-20
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Literature Cited

  1. Abate-Daga D, Davila ML. 2016. CAR models: next-generation CAR modifications for enhanced T-cell function. Mol. Ther. Oncolytics 3:16014
     [Google Scholar]
  2. Alfei F, Kanev K, Hofmann M, Wu M, Ghoneim HE et al. 2019. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571:7764265–69
     [Google Scholar]
  3. Allard B, Pommey S, Smyth MJ, Stagg J 2013. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin. Cancer Res. 19:205626–35
     [Google Scholar]
  4. Amiel E, Everts B, Fritz D, Beauchamp S, Ge B et al. 2014. Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J. Immunol. 193:62821–30
     [Google Scholar]
  5. Angelin A, Gil-de-Gómez 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 25:61282–93.e7
     [Google Scholar]
  6. Austin S, St-Pierre J. 2012. PGC1α and mitochondrial metabolism—emerging concepts and relevance in ageing and neurodegenerative disorders. J. Cell Sci. 125:4963–71
     [Google Scholar]
  7. Bachem A, Makhlouf C, Binger KJ, de Souza DP, Tull D et al. 2019. Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity 1:2285–97.e5
     [Google Scholar]
  8. Balmer ML, Ma EH, Bantug GR, Grählert J, Pfister S et al. 2016. Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44:61312–24
     [Google Scholar]
  9. Baseler WA, Davies LC, Quigley L, Ridnour LA, Weiss JM et al. 2016. Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production. Redox Biol 10:12–23
     [Google Scholar]
  10. Basit F, Mathan T, Sancho D, de Vries JM 2018. Human dendritic cell subsets undergo distinct metabolic reprogramming for immune response. Front. Immunol. 9:2489
     [Google Scholar]
  11. Baumann T, Dunkel A, Schmid C, Schmitt S, Hiltensperger M et al. 2020. Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal. Nat. Immunol. 21:5555–66
     [Google Scholar]
  12. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE et al. 2016. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45:2358–73
     [Google Scholar]
  13. Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S et al. 2020. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 585:7824277–82
     [Google Scholar]
  14. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G et al. 2015. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42:141–54
     [Google Scholar]
  15. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M et al. 2018. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172:51022–37.e14
     [Google Scholar]
  16. Boussiotis VA. 2016. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375:181767–78
     [Google Scholar]
  17. 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]
  18. Bronte V, Kasic T, Gri G, Gallana K, Borsellino G et al. 2005. Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers. J. Exp. Med. 201:81257–68
     [Google Scholar]
  19. 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 166:163–76
     [Google Scholar]
  20. Buck MD, Sowell RT, Kaech SM, Pearce EL 2017. Metabolic instruction of immunity. Cell 169:4570–86
     [Google Scholar]
  21. Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K et al. 2018. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24:81192–203
     [Google Scholar]
  22. Calcinotto A, Filipazzi P, Grioni M, Iero M, De Milito A et al. 2012. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res 72:112746–56
     [Google Scholar]
  23. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E et al. 2010. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185:21037–44
     [Google Scholar]
  24. Cekic C, Day YJ, Sag D, Linden J 2014. Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment. Cancer Res 74:247250–59
     [Google Scholar]
  25. Chaix A, Manoogian ENC, Melkani GC, Panda S 2019. Time-restricted eating to prevent and manage chronic metabolic diseases. Annu. Rev. Nutr. 39:291–315
     [Google Scholar]
  26. 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 153:61239–51
     [Google Scholar]
  27. 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 162:61229–41
     [Google Scholar]
  28. Choi BK, Lee DY, Lee DG, Kim YH, Kim S-H et al. 2017. 4–1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. Cell. Mol. Immunol. 14:9748–57
     [Google Scholar]
  29. Chowdhury PS, Chamoto K, Kumar A, Honjo T 2018. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8+ T cells and facilitates anti-PD-1 therapy. Cancer Immunol. Res. 6:111375–87
     [Google Scholar]
  30. Colegio OR, Chu N-Q, Szabo AL, Chu T, Rhebergen AM et al. 2014. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 513:7519559–63
     [Google Scholar]
  31. Collins N, Han SJ, Enamorado M, Link VM, Huang B et al. 2019. The bone marrow protects and optimizes immunological memory during dietary restriction. Cell 178:1088–101.e15
     [Google Scholar]
  32. Cong J, Wang X, Zheng X, Wang D, Fu B et al. 2018. Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab 28:2243–55.e5
     [Google Scholar]
  33. Cordes T, Wallace M, Michelucci A, Divakaruni AS, Sapcariu SC et al. 2016. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291:2714274–84
     [Google Scholar]
  34. David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE et al. 2014. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505:7484559–63
     [Google Scholar]
  35. DeBerardinis RJ, Chandel NS. 2020. We need to talk about the Warburg effect. Nat. Metab. 2:127–29
     [Google Scholar]
  36. Demeure CE, Yang LP, Desjardins C, Raynauld P, Delespesse G 1997. Prostaglandin E2 primes naive T cells for the production of anti-inflammatory cytokines. Eur. J. Immunol. 27:123526–31
     [Google Scholar]
  37. Di Biase S, Lee C, Brandhorst S, Manes B, Buono R et al. 2016. Fasting-mimicking diet reduces HO-1 to promote T cell-mediated tumor cytotoxicity. Cancer Cell 30:1136–46
     [Google Scholar]
  38. Dumauthioz N, Tschumi B, Wenes M, Marti B, Wang H et al. 2020. Enforced PGC-1α expression promotes CD8 T cell fitness, memory formation and antitumor immunity. Cell. Mol. Immunol. In press. https://doi.org/10.1038/s41423-020-0365-3
    [Crossref] [Google Scholar]
  39. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H 2015. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. PNAS 112:61809–14
     [Google Scholar]
  40. 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 537:7621539–43
     [Google Scholar]
  41. Everts B, Amiel E, Huang SC-C, Smith AM, Chang C-H et al. 2014. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation. Nat. Immunol. 15:323–32
     [Google Scholar]
  42. Everts B, Amiel E, van der Windt GJW, Freitas TC, Chott R et al. 2012. Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120:71422–31
     [Google Scholar]
  43. Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM et al. 2020. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab 31:422–37.e5
     [Google Scholar]
  44. 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 109:93812–19
     [Google Scholar]
  45. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC et al. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:6769–77
     [Google Scholar]
  46. Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB 2002. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J. Exp. Med. 196:4459–68
     [Google Scholar]
  47. Gao X, Sanderson SM, Dai Z, Reid MA, Cooper DE et al. 2019. Dietary methionine influences therapy in mouse cancer models and alters human metabolism. Nature 572:397–401
     [Google Scholar]
  48. 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 167:3829–42.e13
     [Google Scholar]
  49. Gobert AP, Daulouede S, Lepoivre M, Boucher JL, Bouteille B et al. 2000. l-Arginine availability modulates local nitric oxide production and parasite killing in experimental trypanosomiasis. Infect. Immun. 68:84653–57
     [Google Scholar]
  50. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC et al. 2018. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:637197–103
     [Google Scholar]
  51. Griffiths M, Keast D. 1990. The effect of glutamine on murine splenic leukocyte responses to T and B cell mitogens. Immunol. Cell Biol. 68:6405–8
     [Google Scholar]
  52. Guak H, Al Habyan S, Ma EH, Aldossary H, Al-Masri M et al. 2018. Glycolytic metabolism is essential for CCR7 oligomerization and dendritic cell migration. Nat. Commun. 9:2463
     [Google Scholar]
  53. Gubin MM, Zhang X, Schuster H, Caron E, Ward JP et al. 2014. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:7528577–81
     [Google Scholar]
  54. Gubser PM, Bantug GR, Razik L, Fischer M, Dimeloe S et al. 2013. Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14:101064–72
     [Google Scholar]
  55. Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T et al. 2015. Lactate regulates metabolic and proinflammatory circuits in control of T cell migration and effector functions. PLOS Biol 13:7e1002202
     [Google Scholar]
  56. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF et al. 2012. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15:6813–26
     [Google Scholar]
  57. Hatae R, Chamoto K, Kim YH, Sonomura K, Taneishi K et al. 2020. Combination of host immune metabolic biomarkers for the PD-1 blockade cancer immunotherapy. JCI Insight 5:2133501
     [Google Scholar]
  58. Ho P-C, Bihuniak JD, Macintyre AN, Staron M, Liu X et al. 2015. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:61217–28
     [Google Scholar]
  59. Hopkins BD, Pauli C, Xing D, Wang DG, Li X et al. 2018. Suppression of insulin feedback enhances the efficacy of PI3K inhibitors. Nature 560:499–503
     [Google Scholar]
  60. Huang S, Apasov S, Koshiba M, Sitkovsky M 1997. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90:41600–10
     [Google Scholar]
  61. Hudson WH, Gensheimer J, Hashimoto M, Wieland A, Valanparambil RM et al. 2019. Proliferating transitory T cells with an effector-like transcriptional signature emerge from PD-1+ stem-like CD8+ T cells during chronic infection. Immunity 51:61043–58.e4
     [Google Scholar]
  62. Hui E, Cheung J, Zhu J, Su X, Taylor MJ et al. 2017. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355:63321428–33
     [Google Scholar]
  63. Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:7678115–18
     [Google Scholar]
  64. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT et al. 2016. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537:7620417–21
     [Google Scholar]
  65. Infantino V, Iacobazzi V, Menga A, Avantaggiati ML, Palmieri F 2014. A key role of the mitochondrial citrate carrier (SLC25A1) in TNFα- and IFNγ-triggered inflammation. Biochim. Biophys. Acta Gene Regul. Mech. 1839:111217–25
     [Google Scholar]
  66. Infantino V, Iacobazzi V, Palmieri F, Menga A 2013. ATP-citrate lyase is essential for macrophage inflammatory response. Biochem. Biophys. Res. Commun. 440:1105–11
     [Google Scholar]
  67. Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B et al. 2008. Hypoxia and hypoxia-inducible factor-1α modulate lipopolysaccharide-induced dendritic cell activation and function. J. Immunol. 180:74697–705
     [Google Scholar]
  68. Jha AK, Huang SC-C, 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 42:3419–30
     [Google Scholar]
  69. 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]
  70. Jordan S, Tung N, Casanova-Acebes M, Chang C, Cantoni C et al. 2019. Dietary intake regulates the circulating inflammatory monocyte pool. Cell 178:51102–14.e17
     [Google Scholar]
  71. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR et al. 2007. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27:2281–95
     [Google Scholar]
  72. Kamphorst AO, Wieland A, Nasti T, Yang S, Zhang R et al. 2017. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355:63321423–27
     [Google Scholar]
  73. Kanarek N, Petrova B, Sabatini DM 2020. Dietary modifications for enhanced cancer therapy. Nature 579:507–17
     [Google Scholar]
  74. 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]
  75. Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K et al. 2016. Metabolic reprogramming supports IFN-γ production by CD56 bright NK cells. J. Immunol. 196:62552–60
     [Google Scholar]
  76. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF et al. 2019. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571:7764211–18
     [Google Scholar]
  77. Kishton RJ, Sukumar M, Restifo NP 2017. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab 26:194–109
     [Google Scholar]
  78. 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]
  79. Klein Geltink RI, O'Sullivan D, Corrado M, Bremser A, Buck MD et al. 2017. Mitochondrial priming by CD28. Cell 171:2385–97.e11
     [Google Scholar]
  80. Komiya T, Huang CH. 2018. Updates in the clinical development of Epacadostat and other indoleamine 2,3-dioxygenase 1 inhibitors (IDO1) for human cancers. Front. Oncol. 8:423
     [Google Scholar]
  81. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E et al. 2010. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115:234742–49
     [Google Scholar]
  82. Kurniawan H, Franchina DG, Guerra L, Bonetti L, Soriano-Baguet L et al. 2020. Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab 31:5920–36.e7
     [Google Scholar]
  83. Lampropoulou V, Sergushichev A, Bambouskova M, Nair S, Vincent EE et al. 2016. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24:1158–66
     [Google Scholar]
  84. Lau AN, Vander Heiden MG 2020. Metabolism in the tumor microenvironment. Annu. Rev. Cancer Biol. 4:17–40
     [Google Scholar]
  85. Leone RD, Zhao L, Englert JM, Sun I-M, Oh M-H et al. 2019. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366:64681013–21
     [Google Scholar]
  86. Li H, Courtois ET, Sengupta D, Tan Y, Chen KH et al. 2017. Reference component analysis of single-cell transcriptomes elucidates cellular heterogeneity in human colorectal tumors. Nat. Genet. 49:5708–18
     [Google Scholar]
  87. Liu X, Romero IL, Litchfield LM, Lengyel E, Locasale JW 2016. Metformin targets central carbon metabolism and reveals mitochondrial requirements in human cancers. Cell Metab 24:5728–39
     [Google Scholar]
  88. Loftus RM, Assmann N, Kedia-Mehta N, O'Brien KL, Garcia A et al. 2018. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice. Nat. Commun. 9:2341
     [Google Scholar]
  89. Luan B, Yoon Y-S, Le Lay J, Kaestner KH, Hedrick S, Montminy M 2015. CREB pathway links PGE2 signaling with macrophage polarization. PNAS 112:5115642–47
     [Google Scholar]
  90. Lum JJ, Bui T, Gruber M, Gordan JD, DeBerardinis RJ et al. 2007. The transcription factor HIF-1 plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis. Genes Dev 21:91037–49
     [Google Scholar]
  91. Lussier DM, Woolf EC, Johnson JL, Brooks KS, Blattman JN, Scheck AC 2016. Enhanced immunity in a mouse model of malignant glioma is mediated by a therapeutic ketogenic diet. BMC Cancer 16:1310
     [Google Scholar]
  92. Lyssiotis CA, Kimmelman AC. 2017. Metabolic interactions in the tumor microenvironment. Trends Cell Biol 11:11923–26
     [Google Scholar]
  93. 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 25:2345–57
     [Google Scholar]
  94. Ma EH, Verway MJ, Johnson RM, Roy DG, Steadman M et al. 2019. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 51:5856–70.e5
     [Google Scholar]
  95. 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 30:1143–56.e5
     [Google Scholar]
  96. Maddocks ODK, Athineos D, Cheung EC, Lee P, Zhang T et al. 2017. Modulating the therapeutic response of tumours to dietary serine and glycine starvation. Nature 544:372–76
     [Google Scholar]
  97. Magrì A, Germano G, Lorenzato A, Lamba S, Chilà R et al. 2020. High-dose vitamin C enhances cancer immunotherapy. Sci. Transl. Med. 12:532eaay8707
     [Google Scholar]
  98. Maj T, Wang W, Crespo J, Zhang H, Wang W et al. 2017. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat. Immunol. 18:121332–41
     [Google Scholar]
  99. Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y et al. 2017. Glutathione primes T cell metabolism for inflammation. Immunity 46:4675–89
     [Google Scholar]
  100. Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y et al. 2018. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:6371104–8
     [Google Scholar]
  101. 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 22:61509–21
     [Google Scholar]
  102. 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. 215:41091–100
     [Google Scholar]
  103. Michelet X, Dyck L, Hogan A, Loftus RM, Duquette D et al. 2018. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19:121330–40
     [Google Scholar]
  104. Michelucci A, Cordes T, Ghelfi J, Pailot A, Reiling N et al. 2013. Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production. PNAS 110:197820–25
     [Google Scholar]
  105. Miller BC, Sen DR, Al Abosy R, Bi K, Virkud YV et al. 2019. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20:3326–36
     [Google Scholar]
  106. Mills EL, Kelly B, Logan A, Costa ASH, Varma M et al. 2016. Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167:2457–70.e13
     [Google Scholar]
  107. Mittal D, Young A, Stannard K, Yong M, Teng MWL et al. 2014. Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res 74:143652–58
     [Google Scholar]
  108. Muir A, Danai LV, Gui DY, Waingarten CY, Lewis CA, Vander Heiden MG 2017. Environmental cystine drives glutamine anaplerosis and sensitizes cancer cells to glutaminase inhibition. eLife 6:e27713
     [Google Scholar]
  109. Munn DH, Mellor AL. 2016. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 37:3193–207
     [Google Scholar]
  110. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y et 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]
  111. Murray PJ, Wynn TA. 2011. Protective and pathogenic functions of macrophage subsets. Nature 11:723–37
     [Google Scholar]
  112. Nagai M, Noguchi R, Takahashi D, Morikawa T, Koshida K et al. 2019. Fasting-refeeding impacts immune cell dynamics and mucosal immune responses. Cell 178:51072–87.e14
     [Google Scholar]
  113. Novitskiy SV, Ryzhov S, Zaynagetdinov R, Goldstein AE, Huang Y et al. 2008. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112:51822–31
     [Google Scholar]
  114. O'Neill LAJ, Kishton RJ, Rathmell J 2016. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16:553–65
     [Google Scholar]
  115. O'Neill LAJ, Pearce EJ. 2016. Immunometabolism governs dendritic cell and macrophage function. J. Exp. Med. 213:115–23
     [Google Scholar]
  116. Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ 2015. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J. Exp. Med. 212:71125–37
     [Google Scholar]
  117. Olenchock BA, Rathmell JC, Vander Heiden MG 2017. Biochemical underpinnings of immune cell metabolic phenotypes. Immunity 46:5703–13
     [Google Scholar]
  118. Paley MA, Kroy DC, Odorizzi PM, Johnnidis JB, Dolfi DV et al. 2012. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338:61111220–25
     [Google Scholar]
  119. Pan Y, Tian T, Park CO, Lofftus SY, Mei S et al. 2017. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543:7644252–56
     [Google Scholar]
  120. 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. 25:219543–53
     [Google Scholar]
  121. 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]
  122. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H et al. 2009. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:7251103–7
     [Google Scholar]
  123. Pietrocola F, Pol J, Vacchelli E, Rao S, Enot DP et al. 2016. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30:1147–60
     [Google Scholar]
  124. Pinkus LM. 1977. Glutamine binding sites. Methods Enzymol 46:C414–27
     [Google Scholar]
  125. 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]
  126. Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K et al. 2019. Lactate buildup at the site of chronic inflammation promotes disease by inducing CD4+ T cell metabolic rewiring. Cell Metab 30:61055–74.e8
     [Google Scholar]
  127. 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 27:72063–74.e5
     [Google Scholar]
  128. Qualls JE, Subramanian C, Rafi W, Smith AM, Balouzian L et al. 2012. Sustained generation of nitric oxide and control of mycobacterial infection requires argininosuccinate synthase 1. Cell Host Microbe 12:3313–23
     [Google Scholar]
  129. Rabbani N, Thornalley PJ. 2015. Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease. Biochem. Biophys. Res. Commun. 458:2221–26
     [Google Scholar]
  130. 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 51:3548–60.e4
     [Google Scholar]
  131. Rodriguez AE, Ducker GS, Billingham LK, Martinez CA, Mainolfi N et al. 2019. Serine metabolism supports macrophage IL-1β production. Cell Metab 29:41003–11.e4
     [Google Scholar]
  132. Rodríguez-Prados J-C, Través PG, Cuenca J, Rico D, Aragonés J et al. 2010. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185:1605–14
     [Google Scholar]
  133. Ron-Harel N, Ghergurovich JM, Notarangelo G, LaFleur MW, Tsubosaka Y et al. 2019. T cell activation depends on extracellular alanine. Cell Rep 28:123011–21.e4
     [Google Scholar]
  134. Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A et al. 2016. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 24:1104–17
     [Google Scholar]
  135. Rosenberg SA, Restifo NP. 2015. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348:632062–68
     [Google Scholar]
  136. Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT et al. 2018. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:637191–97
     [Google Scholar]
  137. Roy DG, Chen J, Mamane V, Ma EH, Muhire BM et al. 2020. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab 31:2250–66.e9
     [Google Scholar]
  138. Rubio-Patiño C, Bossowski JP, De Donatis GM, Mondragón L, Villa E et al. 2018. Low-protein diet induces IRE1α-dependent anticancer immunosurveillance. Cell Metab 27:4828–42.e7
     [Google Scholar]
  139. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ et al. 2017. CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci. Rep. 7:737
     [Google Scholar]
  140. Sabharwal SS, Rosen DB, Grein J, Tedesco D, Joyce-Shaikh B et al. 2018. GITR agonism enhances cellular metabolism to support CD8+ T-cell proliferation and effector cytokine production in a mouse tumor model. Cancer Immunol. Res. 6:101199–211
     [Google Scholar]
  141. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE et al. 2016a. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:2374–88
     [Google Scholar]
  142. Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM 2016b. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol. Res. 5:19–16
     [Google Scholar]
  143. Schvartzman JM, Thompson CB, Finley LWS 2018. Metabolic regulation of chromatin modifications and gene expression. J. Cell Biol. 217:72247–59
     [Google Scholar]
  144. Scott AC, Dündar F, Zumbo P, Chandran SS, Klebanoff CA et al. 2019. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571:7764270–74
     [Google Scholar]
  145. Seim GL, Britt EC, John SV, Yeo FJ, Johnson AR et al. 2019. Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation. Nat. Metab. 1:7731–42
     [Google Scholar]
  146. Seo H, Chen J, González-Avalos E, Samaniego-Castruita D, Das A et al. 2019. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. PNAS 116:2512410–15
     [Google Scholar]
  147. Sharma S, Yang S-C, Zhu L, Reckamp K, Gardner B et al. 2005. Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+CD25+ T regulatory cell activities in lung cancer. Cancer Res 65:125211–20
     [Google Scholar]
  148. Siddiqui I, Schaeuble K, Chennupati V, Fuertes Marraco SA, Calderon-Copete S et al. 2019. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50:1195–211.e10
     [Google Scholar]
  149. Sinclair LV, Howden AJM, Brenes A, Spinelli L, Hukelmann JL et al. 2019. Antigen receptor control of methionine metabolism in T cells. eLife 8:e44210
     [Google Scholar]
  150. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA 2013. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14:5500–8
     [Google Scholar]
  151. Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W et al. 2016. Suppression of Glut1 and glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in B cell leukemia. J. Immunol. 197:62532–40
     [Google Scholar]
  152. Snijdewint FG, Kaliński P, Wierenga EA, Bos JD, Kapsenberg ML 1993. Prostaglandin E2 differentially modulates cytokine secretion profiles of human T helper lymphocytes. J. Immunol. 150:125321–29
     [Google Scholar]
  153. Speiser DE, Ho PC, Verdeil G 2016. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16:10599–611
     [Google Scholar]
  154. Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL et al. 2020. CRISPR-engineered T cells in patients with refractory cancer. Science 367:6481eaba736
     [Google Scholar]
  155. Stagg J, Divisekera U, Duret H, Sparwasser T, Teng MWL et al. 2011. CD73-deficient mice have increased antitumor immunity and are resistant to experimental metastasis. Cancer Res 71:82892–900
     [Google Scholar]
  156. 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. 123:104479–88
     [Google Scholar]
  157. 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]
  158. Tannahill GM, Curtis AM, Adamik J, Palsson-Mcdermott EM, McGettrick AF et al. 2013. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:7444238–42
     [Google Scholar]
  159. 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. 36:8758–64
     [Google Scholar]
  160. Trompette A, Gollwitzer ES, Pattaroni C, Lopez-Mejia IC, Riva E et al. 2018. Dietary fiber confers protection against flu by shaping Ly6c− patrolling monocyte hematopoiesis and CD8+ T cell metabolism. Immunity 48:5992–1005.e8
     [Google Scholar]
  161. Tsai S, Clemente-Casares X, Zhou AC, Lei H, Ahn JJ et al. 2018. Insulin receptor-mediated stimulation boosts T cell immunity during inflammation and infection. Cell Metab 28:6922–34.e4
     [Google Scholar]
  162. Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT et al. 2016. S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate. Nature 540:7632236–41
     [Google Scholar]
  163. Vaeth M, Maus M, Klein-Hessling S, Freinkman E, Yang J et al. 2017. Store-operated Ca2+ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity 47:664–79
     [Google Scholar]
  164. Van den Bossche J, Baardman J, Otto NA, van der Velden S, Neele AE et al. 2016. Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep 17:3684–96
     [Google Scholar]
  165. Van Den Eynde BJ, Van Baren N, Baurain JF 2020. Is there a clinical future for IDO1 inhibitors after the failure of epacadostat in melanoma. ? Annu. Rev. Cancer Biol. 4:241–56
     [Google Scholar]
  166. van der Windt GJW, Everts B, Chang CH, Curtis JD, Freitas TC et al. 2012. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36:168–78
     [Google Scholar]
  167. 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]
  168. Vijayan D, Young A, Teng MWL, Smyth MJ 2017. Targeting immunosuppressive adenosine in cancer. Nat. Rev. Cancer 17:709–24
     [Google Scholar]
  169. Vodnala SK, Eil R, Kishton RJ, Sukumar M, Yamamoto TN et al. 2019. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363:6434eaau0135
     [Google Scholar]
  170. Wang C, Yosef N, Gaublomme J, Wu C, Lee Y et al. 2015. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163:61413–27
     [Google Scholar]
  171. 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. 21:3298–308
     [Google Scholar]
  172. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R et al. 2011. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:6871–82
     [Google Scholar]
  173. Wang T, Gnanaprakasam JNR, Chen X, Kang S, Xu X et al. 2020. Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction. Nat. Metab. 2:635–47
     [Google Scholar]
  174. Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM et al. 2019. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565:495–99
     [Google Scholar]
  175. Wherry EJ, Ha SJ, Kaech SM, Haining WN, Sarkar S et al. 2007. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27:4670–84
     [Google Scholar]
  176. Wherry EJ, Kurachi M. 2015. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15:8486–99
     [Google Scholar]
  177. Wolf T, Jin W, Zoppi G, Vogel IA, Akhmedov M et al. 2020. Dynamics in protein translation sustaining T cell preparedness. Nat. Immunol. 21:927–37
     [Google Scholar]
  178. Wu D, Wong CK, Han JM, Orban PC, Huang Q et al. 2020. T reg–specific insulin receptor deletion prevents diet-induced and age-associated metabolic syndrome. J. Exp. Med. 217:8e20191542
     [Google Scholar]
  179. Xiao Z, Dai Z, Locasale JW 2019. Metabolic landscape of the tumor microenvironment at single cell resolution. Nat. Commun. 10:13763
     [Google Scholar]
  180. 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 531:7596651–55
     [Google Scholar]
  181. Yao C, Sun HW, Lacey NE, Ji Y, Moseman EA et al. 2019. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20:7890–901
     [Google Scholar]
  182. Young A, Ngiow SF, Gao Y, Patch AM, Barkauskas DS et al. 2018. A2AR adenosine signaling suppresses natural killer cell maturation in the tumor microenvironment. Cancer Res 78:41003–16
     [Google Scholar]
  183. Zanin RF, Braganhol E, Bergamin LS, Campesato LFI, Filho AZ et al. 2012. Differential macrophage activation alters the expression profile of NTPDase and ecto-5′-nucleotidase. PLOS ONE 7:2e31205
     [Google Scholar]
  184. Zannella VE, Pra AD, Muaddi H, McKee TD, Stapleton S et al. 2013. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin. Cancer Res. 19:246741–50
     [Google Scholar]
  185. Zelenay S, van der Veen AG, Böttcher JP, Snelgrove KJ, Rogers N et al. 2015. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162:61257–70
     [Google Scholar]
  186. Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G et al. 2017. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32:3377–91.e9
     [Google Scholar]
  187. Zhao E, Maj T, Kryczek I, Li W, Wu K et al. 2016. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17:195–103
     [Google Scholar]
  188. Zhou X, Yu S, Zhao DM, Harty JT, Badovinac VP, Xue HH 2010. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 33:2229–40
     [Google Scholar]
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Immunometabolism in the Tumor Microenvironment
Annual Review of Cancer Biology 5, 137 (2021); https://doi.org/10.1146/annurev-cancerbio-030518-055817
/content/journals/10.1146/annurev-cancerbio-030518-055817
/content/journals/10.1146/annurev-cancerbio-030518-055817
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