Volume 27, Issue 1 (1-2023)                   IBJ 2023, 27(1): 1-14 | Back to browse issues page

PMID: 36624636


XML Print


Abstract:  
Immunometabolism is an emerging field in tumor immunotherapy. Understanding the metabolic competition for access to the limited nutrients between tumor cells and immune cells can reveal the complexity of the tumor microenvironment and help develop new therapeutic approaches for cancer. Recent studies have focused on modifying the function of immune cells by manipulating their metabolic pathways. Besides, identifying metabolic events, which affect the function of immune cells leads to new therapeutic opportunities for treatment of inflammatory diseases and immune-related conditions. According to the literature, metabolic pathway such as glycolysis, tricarboxylic acid cycle, and fatty acid metabolism, significantly influence the survival, proliferation, activation, and function of immune cells and thus regulate immune responses. In this paper, we reviewed the role of metabolic processes and major signaling pathways involving in T-cell regulation and T-cell responses against tumor cells. Moreover, we summarized the new therapeutics suggested to enhance anti-tumor activity of T cells through manipulating metabolic pathways.

References
1. Thiele K, Diao L, Arck PC, editors. Immunometabolism, pregnancy, and nutrition. Seminars in immunopathology 2018: 40(2): 157-174. [DOI:10.1007/s00281-017-0660-y]
2. Wang Q, Wu H. T cells in adipose tissue: critical players in immunometabolism. Frontiers in immunology 2018; 9: 2509. [DOI:10.3389/fimmu.2018.02509]
3. Man K, Kutyavin VI, Chawla A. Tissue immunometabolism: development, physiology, and pathobiology. Cell metabolism 2017; 25(1): 11-26. [DOI:10.1016/j.cmet.2016.08.016]
4. Ryan DG, O'Neill LA. Krebs cycle reborn in macrophage immunometabolism. Annual review of immunology 2020; 38: 289-313. [DOI:10.1146/annurev-immunol-081619-104850]
5. Ramalho R, Rao M, Zhang C, Agrati C, Ippolito G, Wang FS. editors. Immunometabolism: new insights and lessons from antigen-directed cellular immune responses. Seminars in هmmunopathology 2020; 42(3): 279-313. [DOI:10.1007/s00281-020-00798-w]
6. O'Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nature reviews immunology 2016; 16(9): 553-565. [DOI:10.1038/nri.2016.70]
7. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, Giamarellos-Bourboulis EJ, Martens JHA, Appukudige Rao N, Aghajanirefah A, Manjeri GR, Li Y, Ifrim DC, Arts RJW, van der Veer BMJW, Deen PMT, Logie C, O'Neill LA, Willems P, Ng A, Joosten LAB, Wijmenga C, Stunnenberg HG, Xavier RJ, Netea MG. mTOR-and HIF-1α-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 2014; 345(6204): 1250684. [DOI:10.1126/science.1250684]
8. McGuire PJ. Chemical individuality in T cells: a Garrodian view of immunometabolism. Immunological reviews 2020; 295(1): 82-100. [DOI:10.1111/imr.12854]
9. Akram M. Citric acid cycle and role of its intermediates in metabolism. Cell biochemistry and biophysics 2014; 68(3): 475-478. [DOI:10.1007/s12013-013-9750-1]
10. Watmough NJ, Frerman FE. The electron transfer flavoprotein: ubiquinone oxidoreductases. Biochimica et biophysica acta 2010; 1797(12): 1910-1916. [DOI:10.1016/j.bbabio.2010.10.007]
11. Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nature reviews cancer 2016; 16(11): 732-749. [DOI:10.1038/nrc.2016.89]
12. Holecek M, Vodenicarovova M, Siman P. Acute effects of phenylbutyrate on glutamine, branched-chain amino acid and protein metabolism in skeletal muscles of rats. International journal of experimental pathology 2017; 98(3): 127-133. [DOI:10.1111/iep.12231]
13. Saravia J, Raynor JL, Chapman NM, Lim SA, Chi H. Signaling networks in immunometabolism. Cell research 2020; 30(4): 328-342. [DOI:10.1038/s41422-020-0301-1]
14. Chapman NM, Boothby MR, Chi H. Metabolic coordination of T cell quiescence and activation. Nature reviews immunology 2020; 20(1): 55-70. [DOI:10.1038/s41577-019-0203-y]
15. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, Magnuson MA, Boothby M. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010; 32(6): 743-753. [DOI:10.1016/j.immuni.2010.06.002]
16. Li N, Huang D, Lu N, Luo L. Role of the LKB1/AMPK pathway in tumor invasion and metastasis of cancer cells. Oncology reports 2015; 34(6): 2821-2816. [DOI:10.3892/or.2015.4288]
17. Shahouzehi B, Fallah H, Masoumi-Ardakani Y. L-carnitine administration effects on AMPK, APPL1 and PPARγ genes expression in the liver and serum adiponectin levels and HOMA-IR in type 2 diabetes rat model induced by STZ and nicotinamide. Ukrainian biochemical journal 2020; 95(5): 33-40. [DOI:10.15407/ubj92.05.033]
18. Zhang CS, Hawley SA, Zong Y, Li M, Wang Z, Gray A, Ma T, Cui J, Feng J-W, Zhu M, Wu YQ, Yang Li T, Ye Z, Lin SY, Yin H, Piao HL, Grahame Hardie D, Lin SC. Fructose-1, 6-bisphosphate and aldolase mediate glucose sensing by AMPK. Nature 2017; 548(7665): 112-116. [DOI:10.1038/nature23275]
19. Mohammadi A, Fallah H, Shahouzehi B, Najafipour H. Effect of LXR agonist T0901317 and miR-33inhibitor on SIRT1-AMPK and circulating HDL-C levels. Bulg chem commun 2018; 50(1): 111-118.
20. Timilshina M, You Z, Lacher SM, Acharya S, Jiang L, Kang Y, Kim J, Wook Chang H, Kim KJ, Park B, Song JH , Ko HJ, Park YY, Ma MJ, Nepal MR, Cheon Jeong T, Chung Y, Waisman A, Chang JH. Activation of mevalonate pathway via LKB1 is essential for stability of Treg cells. Cell reports 2019; 27(10): 2948-2961. [DOI:10.1016/j.celrep.2019.05.020]
21. Poznanski SM, Barra NG, Ashkar AA, Schertzer JD. Immunometabolism of T cells and NK cells: metabolic control of effector and regulatory function. Inflammation research 2018; 67(10): 813-828. [DOI:10.1007/s00011-018-1174-3]
22. Ciofani M, Zuniga-Pflücker JC. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nature immunology 2005; 6(9): 881-888. [DOI:10.1038/ni1234]
23. Swainson L, Kinet S, Manel N, Battini JL, Sitbon M, Taylor N. Glucose transporter 1 expression identifies a population of cycling CD4+ CD8+ human thymocytes with high CXCR4-induced chemotaxis. Proceedings of the national academy of sciences 2005; 102(36):12867-12872. [DOI:10.1073/pnas.0503603102]
24. Vigano MA, Ivanek R, Balwierz P, Berninger P, van Nimwegen E, Karjalainen K, Rolink V. An epigenetic profile of early T-cell development from multipotent progenitors to committed T-cell descendants. European journal of immunology 2014; 44(4): 1181-1193. [DOI:10.1002/eji.201344022]
25. Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 2016; 354(6311): 481-484. [DOI:10.1126/science.aaf6284]
26. Ron Harel N, Sharpe AH, Haigis MC. Mitochondrial metabolism in T cell activation and senescence: a mini-review. Gerontology 2015; 61(2): 131-138. [DOI:10.1159/000362502]
27. Chang CH, Curtis JD, Maggi Jr LB, Faubert B, Villarino AV, O'Sullivan D, Ching Cheng Huang S, van der Windt GJV, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153(6): 1239-12351. [DOI:10.1016/j.cell.2013.05.016]
28. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. The Journal of immunology 2011; 186(6): 3299-3303. [DOI:10.4049/jimmunol.1003613]
29. Jones N, Cronin JG, Dolton G, Panetti S, Schauenburg AJ, Galloway SA, Sewell AK, Cole DK, Thornton CA, Francis NJ. Metabolic adaptation of human CD4+ and CD8+ T-cells to T-cell receptor-mediated stimulation. Frontiers in immunology 2017; 8: 1516. [DOI:10.3389/fimmu.2017.01516]
30. 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. Journal of experimental and clinical cancer research 2019; 38(1): 1-10. [DOI:10.1186/s13046-019-1409-3]
31. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. Journal of experimental medicine 2011; 208(7): 1367-1376. [DOI:10.1084/jem.20110278]
32. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick L, Fitzgerald P, Chi H, Munger J, Green DR. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011; 35(6): 871-882. [DOI:10.1016/j.immuni.2011.09.021]
33. Mahnke J, Schumacher V, Ahrens S, Käding N, Feldhoff LM, Huber M, Rupp J, Raczkowski F, Mittrücker HW. Interferon regulatory factor 4 controls TH1 cell effector function and metabolism. Scientific reports 2016; 6(1): 1-12. [DOI:10.1038/srep35521]
34. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 2015; 162(6): 1217-1228. [DOI:10.1016/j.cell.2015.08.012]
35. Klysz D, Tai X, Robert PA, Craveiro M, Cretenet G, Oburoglu L, Mongellaz C, Floess S, Fritz V, Matias MI, Yong C, Surh N, Marie JC, Huehn J, Zimmermann V, Kinet S, Dardalhon V, Taylor N. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Science signaling. 2015; 8(396): ra97. [DOI:10.1126/scisignal.aab2610]
36. Allocco JB, Alegre ML. Exploiting immunometabolism and T cell function for solid organ transplantation. Cellular immunology 2020; 351: 104068. [DOI:10.1016/j.cellimm.2020.104068]
37. Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014; 40(5): 692-705. [DOI:10.1016/j.immuni.2014.04.007]
38. Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A, Contreras DC, Maseda D, Liberti MV, Paz K, Kishton RJ, Johnson ME, de Cubas AA, Wu R, Li G, Zhang Y, Newcomb DC, Wells AD, Restifo NP, Rathmell WK, Locasale JW, Davila ML, Blazar BR, Rathmell JC. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 2018; 175(7): 1780-1795. [DOI:10.1016/j.cell.2018.10.001]
39. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell metabolism 2014; 20(1): 61-72. [DOI:10.1016/j.cmet.2014.05.004]
40. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bähre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Müller R, Lochner M, Sparwasser T. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nature medicine 2014; 20(11): 1327-1333. [DOI:10.1038/nm.3704]
41. Prlic M, Williams MA, Bevan MJ. Requirements for CD8 T-cell priming, memory generation and maintenance. Current opinion in immunology 2007; 19(3): 315-319. [DOI:10.1016/j.coi.2007.04.010]
42. King CG, Kobayashi T, Cejas PJ, Kim T, Yoon K, Kim GK, Chiffoleau E, Hickman SP, Walsh PT, Turka LA, Choi Y. TRAF6 is a T cell-intrinsic negative regulator required for the maintenance of immune homeostasis. Nature medicine 2006; 12(9): 1088-1092. [DOI:10.1038/nm1449]
43. van der Windt GJ, Everts B, Chang C-H, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012; 36(1): 68-78. [DOI:10.1016/j.immuni.2011.12.007]
44. Beier UH, Angelin A, Akimova T, Wang L, Liu Y, Xiao H, Koike MA , Hancock SA, Bhatti TR, Han R, Jiao J, Veasey SC, Sims CA, Baur JA, Wallace DC, Hancock WW. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. The FASEB journal 2015; 29(6): 2315-2326. [DOI:10.1096/fj.14-268409]
45. Fan MY, Turka LA. Immunometabolism and PI (3) K signaling as a link between IL-2, Foxp3 expression, and suppressor function in regulatory T cells. Frontiers in immunology 2018; 9: 69. [DOI:10.3389/fimmu.2018.00069]
46. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+ CD25+ regulatory T cells. Nature immunology 2003; 4(4): 330-336. [DOI:10.1038/ni904]
47. Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nature immunology 2015; 16(2): 178-187. [DOI:10.1038/ni.3076]
48. Apostolidis SA, Rodríguez-Rodríguez N, Suárez-Fueyo A, Dioufa N, Ozcan E, Crispín JC, Tsokos MG, Tsokos GC. Phosphatase PP2A is requisite for the function of regulatory T cells. Nature immunology 2016; 17(5): 556-564. [DOI:10.1038/ni.3390]
49. Kishton RJ, Sukumar M, Restifo NP. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell metabolism 2017; 26(1): 94-109. [DOI:10.1016/j.cmet.2017.06.016]
50. Leone RD, Powell JD. Metabolism of immune cells in cancer. Nature reviews cancer 2020; 20(9): 516-531. [DOI:10.1038/s41568-020-0273-y]
51. Chang CH, Qiu J, O'Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJW, Tonc E, Schreiber RD, Pearce EJ, Pear EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162(6): 1229-1241. [DOI:10.1016/j.cell.2015.08.016]
52. Yu J, Du W, Yan F, Wang Y, Li H, Cao S, Yu W, Shen C, Liu J, Ren X. Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer. The Journal of immunology 2013; 190(7): 3783-3797. [DOI:10.4049/jimmunol.1201449]
53. Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends in immunology 2016; 37(3): 193-207. [DOI:10.1016/j.it.2016.01.002]
54. Zhai L, Bell A, Ladomersky E, Lauing KL, Bollu L, Nguyen B, Genet M, Kim M, Chen P, Mi X, Wu JD, Schipma MJ, Wray B, Griffiths J, Unwin RD, Clark SJ, Acharya R, Bao R, Horbinski C, Lukas RV, Schiltz G, Wainwright DA. Tumor cell IDO enhances immune suppression and decreases survival independent of tryptophan metabolism in glioblastoma. Clinical cancer research 2021; 27(23): 6514-6528. [DOI:10.1158/1078-0432.CCR-21-1392]
55. Schramme F, Crosignani S, Frederix K, Hoffmann D, Pilotte L, Stroobant V, Preillon J, Driessens G, Van den Eynde BJ. Inhibition of Tryptophan-Dioxygenase Activity Increases the Antitumor Efficacy of Immune Checkpoint InhibitorsAntitumor Synergy Between TDO and Checkpoint Inhibitors. Cancer immunology research 2020; 8(1): 32-45. [DOI:10.1158/2326-6066.CIR-19-0041]
56. Leone RD, Sun IM, Oh M-H, Sun IH, Wen J, Englert J, Powell JD. Inhibition of the adenosine A2a receptor modulates expression of T cell coinhibitory receptors and improves effector function for enhanced checkpoint blockade and ACT in murine cancer models. Cancer immunology, immunotherapy 2018; 67(8): 1271-1284. [DOI:10.1007/s00262-018-2186-0]
57. Ferrante CJ, Pinhal Enfield G, Elson G, Cronstein BN, Hasko G, Outram S, SJ. The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation 2013; 36(4): 921-931. [DOI:10.1007/s10753-013-9621-3]
58. Wang H, Franco F, Tsui YC, Xie X, Trefny MP, Zappasodi R, Mohmood SR, Fernández-García J, Tsai CH, Schulze I, Picard F, Meylan E, Silverstein R, Goldberg I, Fendt SM, Wolchok JD, Merghoub T, Jandus C, Zippelius A, Ho PC. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nature immunology 2020; 21(3): 298-308. [DOI:10.1038/s41590-019-0589-5]
59. Xu S, Chaudhary O, Rodríguez Morales P, Sun X, Chen D, Zappasodi R, Xu Z,.PintoAFM, Williams A, Schulze I, Farsakoglu Y, Karthik Varanasi S, Siong Low J, Tang W, Wang H, McDonald B, Tripple V, Downes M, Evans RM, Abumrad NA, Merghoub T, Wolchok JD, Shokhirev MN, Ho PC, Witztum JL, Emu B, Cui G, Kaech SM. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 2021; 54(7): 1561-1577. [DOI:10.1016/j.immuni.2021.05.003]
60. Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, Corbett M , Rankin AL, Dibella R, Campbell L, Martin GH, Lemar H, Cayton T, Y-C Huang R, Deng X, Nayeem A, Chen H, Ergel B, Rizzo JM, Yamniuk AP, Dutta S, Ngo J, Olga Shorts A, Ramakrishnan R, Kozhich A, Holloway J, Fang H, Wang YK, Yang Z, Thiam K, Rakestraw G, Rajpal A, Sheppard P, Quigley M, Bahjat KS, Korman AJ. VISTA is an acidic pH-selective ligand for PSGL-1. Nature 2019; 574(7779): 565-570. [DOI:10.1038/s41586-019-1674-5]
61. Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, Alansary D, Sonner JK, Green E, Deumelandt K, Kilian M, Neftel C, Uhlig S, Kessler T, von Landenberg A, Berghoff AS, Marsh K, Steadman M, Zhu D, Nicolay B, Wiestler B, Breckwoldt MO, Al Ali R, Karcher-Bausch S. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nature medicine 2018; 24(8): 1192-1203. [DOI:10.1038/s41591-018-0095-6]
62. Eil R, Vodnala SK, Clever D, Klebanoff CA, Sukumar M, Pan JH, Palmer DC, Gros A, Yamamoto TN, Patel SJ, Guittard GC, Yu Z, Carbonaro V, Okkenhaug K, Schrump DS, Marston Linehan W, Roychoudhuri R, Restifo NP. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 2016; 537(7621): 539-543. [DOI:10.1038/nature19364]
63. Kostourou V, Cartwright J, Johnstone A, Boult J, Cullis E, Whitley G, Robinson SP. The role of tumour-derived iNOS in tumour progression and angiogenesis. British journal of cancer 2011; 104(1): 83-90. [DOI:10.1038/sj.bjc.6606034]
64. Grzywa TM, Sosnowska A, Matryba P, Rydzynska Z, Jasinski M, Nowis D, Golab J. Myeloid cell-derived arginase in cancer immune response. Frontiers in immunology 2020; 11: 938. [DOI:10.3389/fimmu.2020.00938]
65. Fletcher M, Ramirez ME, Sierra RA, Raber P, Thevenot P, Al-Khami AA, Sanchez-Pino D, Hernandez C, Wyczechowska DD, Ochoa AC, Rodriguez PC. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells suppression of T-cell responses by L-arginine depletion. Cancer research 2015; 75(2): 275-283. [DOI:10.1158/0008-5472.CAN-14-1491]
66. Liu YN, Yang JF, Huang DJ, Ni HH, Zhang CX, Zhang L, Gao S, Li J. Hypoxia induces mitochondrial defect that promotes T cell exhaustion in tumor microenvironment through MYC-regulated pathways. Frontiers in immunology 2020; 11: 1906. [DOI:10.3389/fimmu.2020.01906]
67. Buck MD, O'Sullivan D, Geltink RIK, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ, Chen Q, Ching Cheng Huang S, O'Neill CM, Edelson BT, Pearce EJ, Sesaki H, Huber TB, Rambold AS, Pearce EL. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 2016; 166(1): 63-76. [DOI:10.1016/j.cell.2016.05.035]
68. Saha T, Dash C, Jayabalan R, Khiste S, Kulkarni A, Kurmi K, Mondal J, Majumder PK, Bardia A, Lin Jang H, Sengupta S. Intercellular nanotubes mediate mitochondrial trafficking between cancer and immune cells. Nature nanotechnology 2022; 17(1): 98-106. [DOI:10.1038/s41565-021-01000-4]
69. Gomez Pinillos A, Ferrari AC. mTOR signaling pathway and mTOR inhibitors in cancer therapy. Hematology/oncology clinics 2012; 26(3): 483-505. [DOI:10.1016/j.hoc.2012.02.014]
70. Yue W, Yang CS, DiPaola RS, Tan XL. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer prevention research 2014; 7(4): 388-397. [DOI:10.1158/1940-6207.CAPR-13-0337]
71. Zaytseva YY, Valentino JD, Gulhati P, Evers BM. mTOR inhibitors in cancer therapy. Cancer letters 2012; 319(1): 1-7. [DOI:10.1016/j.canlet.2012.01.005]
72. Vinay DS, Kwon BS. 4-1BB (CD137), an inducible costimulatory receptor, as a specific target for cancer therapy. BMB reports 2014; 47(3): 122. [DOI:10.5483/BMBRep.2014.47.3.283]
73. Sanchez Paulete AR, Labiano S, Rodriguez Ruiz ME, Azpilikueta A, Etxeberria I, Bolaños E, Lang V, Rodriguez M, Angela Aznar M, Jure-Kunkel M, Melero I. Deciphering CD137 (4-1BB) signaling in T-cell costimulation for translation into successful cancer immunotherapy. European journal of immunology 2016; 46(3): 513-522. [DOI:10.1002/eji.201445388]
74. Choi BK, Lee DY, Lee DG, Kim YH, Kim S-H, Oh HS, Han C, Kwon BS. 4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation. Cellular and molecular immunology 2017; 14(9): 748-757. [DOI:10.1038/cmi.2016.02]
75. Menk AV, Scharping NE, Rivadeneira DB, Calderon MJ, Watson MJ, Dunstane D, Watkins Sc, Delgoffe GM. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immuno-therapeutic responses. Journal of experimental medicine 2018; 215(4): 1091-1100. [DOI:10.1084/jem.20171068]
76. Chester C, Ambulkar S, Kohrt HE. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer immunology, immunotherapy 2016; 65(10): 1243-1248. [DOI:10.1007/s00262-016-1829-2]
77. Ohashi T, Akazawa T, Aoki M, Kuze B, Mizuta K, Ito Y, Inoue N. Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity. International journal of cancer 2013; 133(5): 1107-1118. [DOI:10.1002/ijc.28114]
78. Pilon Thomas S, Kodumudi KN, El Kenawi AE, Russell S, Weber AM, Luddy K, Damaghi M, Wojtkowiak JW, Mulé JJ, Ibrahim Hashim A, Gillies RJ. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer research 2016; 76(6): 1381-1390. [DOI:10.1158/0008-5472.CAN-15-1743]
79. Riley LW, Raphael E, Faerstein E. Obesity in the United States-dysbiosis from exposure to low-dose antibiotics? Frontiers in public health 2013; 1: 69. [DOI:10.3389/fpubh.2013.00069]
80. He Y, Fu L, Li Y, Wang W, Gong M, Zhang J, Dong X, Huang J, Wang Q, Mackay CR, Fu YX, Chen Y, Guo X. Gut microbial metabolites facilitate anticancer therapy efficacy by modulating cytotoxic CD8+ T cell immunity. Cell metabolism 2021; 33(5): 988-1000. [DOI:10.1016/j.cmet.2021.03.002]
81. Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM. The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8+ T cells during chronic infection. Immunity 2014; 41(5): 802-814. [DOI:10.1016/j.immuni.2014.10.013]
82. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L, Boussiotis VA. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nature communications 2015; 6(1): 1-13. [DOI:10.1038/ncomms7692]
83. Previte DM, Martins CP, O'Connor EC, Marre ML, Coudriet GM, Beck NW, Menk AV, Wright RH, Tse HM, Delgoffe GM, Piganelli JD. Lymphocyte activation gene-3 maintains mitochondrial and metabolic quiescence in naive CD4+ T cells. Cell reports 2019; 27(1): 129-141. [DOI:10.1016/j.celrep.2019.03.004]
84. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature reviews cancer 2012; 12(4): 252-264. [DOI:10.1038/nrc3239]
85. Ho PC, Liu PS. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. Journal for immunotherapy of cancer 2016; 4(1): 1-9. [DOI:10.1186/s40425-016-0109-1]
86. Beckermann KE, Dudzinski SO, Rathmell JC. Dysfunctional T cell metabolism in the tumor microenvironment. Cytokine and growth factor reviews 2017; 35: 7-14. [DOI:10.1016/j.cytogfr.2017.04.003]
87. Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, Li CW, Kim T, Chang SS, Lee HH, Hsu GL, Wang HL, Kuo CW, Chang WC, Hadad S, Purdie CA, McCoy AM, Cai S, Tu Y, Litton JK, Mittendorf EA, Moulder SL, Symmans WF, Thompson AM, Piwnica-Worms H, Chen CH, Khoo KH, Hung MC. Metformin promotes antitumor immunity via endoplasmic-reticulum-associated degradation of PD-L1. Molecular cell 2018; 71(4): 606-620. [DOI:10.1016/j.molcel.2018.07.030]
88. Chatterjee S, Chakraborty P, Daenthanasanmak A, Iamsawat S, Andrejeva G, LA L, Wolf M, Baliga U, Krieg C, Beeson CC, Mehrotra M, Hill EG, Rathmell JC, Yu XZ, Kraft AS, Mehrotra S. Targeting PIM kinase with PD1 inhibition improves immuno-therapeutic antitumor T-cell responsePIM-K inhibition potentiates ACT. Clinical cancer research 2019; 25(3): 1036-1049. [DOI:10.1158/1078-0432.CCR-18-0706]
89. Frostegård J, Zhang Y, Sun J, Yan K, Liu A. Oxidized low-density lipoprotein (Ox LDL)-treated dendritic cells promote activation of T cells in human atherosclerotic plaque and blood, which is repressed by statins: micro RNA let-7c is integral to the effect. Journal of the american heart association 2016; 5(9): e003976. [DOI:10.1161/JAHA.116.003976]
90. Gruenbacher G, Thurnher M. Mevalonate metabolism governs cancer immune surveillance. Oncoimmunology 2017; 6(10): e1342917. [DOI:10.1080/2162402X.2017.1342917]
91. Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, Meng X, Li L, Wang J, Xu C, Yan C, Wang L, Chang CCY, Chang TY, Zhang T, Zhou P, Song BL, Liu W, Sun SC, Liu X, Li BL, Xu C. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 2016; 531(7596): 651-655. [DOI:10.1038/nature17412]
92. Mohammadi A, Gholamhosseinian A, Fallah H. Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats. Advanced biomedical research 2016; 5. 54 [DOI:10.4103/2277-9175.178799]
93. Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Filisio F, Giles-Davis W, Xu X, Karakousis GC, Schuchter LM, Xu W, Amaravadi R, Xiao M, Sadek N, Krepler C, Herlyn M, Freeman GJ, Rabinowitz JD, Ertl HCJ. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer cell 2017; 32(3): 377-391. [DOI:10.1016/j.ccell.2017.08.004]
94. Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A, Huang L, Zhao Y, Lin W, Hsueh EC, Shen L, Shao Q, Hoft DF, Ford DA, Peng G. Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Science translational medicine 2021; 13(587): eaaz6314. [DOI:10.1126/scitranslmed.aaz6314]
95. Muller AJ, Manfredi MG, Zakharia Y, Prendergast GC, editors. Inhibiting IDO pathways to treat cancer: lessons from the ECHO-301 trial and beyond. Seminars in immunopathology 2019; 41(1): 41-48. [DOI:10.1007/s00281-018-0702-0]
96. Nayak Kapoor A, Hao Z, Sadek R, Dobbins R, Marshall L, Vahanian NN, Ramsey WJ, Kennedy E, Mautino MR, Link CJ, Lin RS, Royer-Joo S, Liang X, Salphati L, ari M Morrissey K, Mahrus S, McCall B, Pirzkall A, Munn DH, Janik JE, Khleif SN. Phase Ia study of the indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor navoximod (GDC-0919) in patients with recurrent advanced solid tumors. Journal for immunotherapy of cancer 2018; 6(1): 1-12. [DOI:10.1186/s40425-018-0351-9]
97. Beatty GL, O'Dwyer PJ, Clark J, Shi JG, Bowman KJ, Scherle PA, Newton RC, Schaub R, Maleski J, Leopold L, Gajewski TF. First in human phase I study of the oral inhibitor of indoleamine 2,3-Dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clinical cancer research : an official journal of the American association for cancer research 2017; 23(13): 3269-3276. [DOI:10.1158/1078-0432.CCR-16-2272]
98. Spranger S, Koblish HK, Horton B, Scherle PA, Newton R, Gajewski TF. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8+ T cells directly within the tumor micro-environment. Journal for immunotherapy of cancer 2014; 2(1): 1-14. [DOI:10.1186/2051-1426-2-3]
99. Nabe S, Yamada T, Suzuki J, Toriyama K, Yasuoka T, Kuwahara M, Shiraishi A, Takenaka K, Yasukawa M, Yamashita M. Reinforce the antitumor activity of CD 8+ T cells via glutamine restriction. Cancer science 2018; 109(12): 3737-3750. [DOI:10.1111/cas.13827]
100. Sung JY, Cheong JH. New immunometabolic strategy based on cell type-specific metabolic reprogramming in the Tumor Immune Microenvironment. Cells 2022; 11(5): 768. [DOI:10.3390/cells11050768]
101. Scheffel MJ, Scurti G, Wyatt MM, Garrett Mayer E, Paulos CM, Nishimura MI, Voelkel Johnson C. N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner. Cancer immunology, immunotherapy 2018; 67(4): 691-702. [DOI:10.1007/s00262-018-2120-5]
102. Perl A, Hanczko R, Lai ZW, Oaks Z, Kelly R, Borsuk R, Asara JM, Phillips PE. Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation of kynurenine in systemic lupus erythematosus: implications for activation of the mechanistic target of rapamycin. Metabolomics 2015; 11(5): 1157-1174. [DOI:10.1007/s11306-015-0772-0]
103. Edwards DN, Ngwa VM, Raybuck AL, Wang S, Hwang Y, Kim LC, Hoon Cho S, Paik Y, Wang Q, Zhang S, Charles Manning H, Rathmell JC, Cook RS, Boothby MR, Chen J. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. The Journal of clinical investigation 2021; 131(4): e140100. [DOI:10.1172/JCI140100]

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.