Metabolic interventions combined with CTLA-4 and PD-1/PD-L1 blockade for the treatment of tumors: mechanisms and strategies

Abstract

Immunotherapies based on immune checkpoint blockade (ICB) have significantly improved patient outcomes and offered new approaches to cancer therapy over the past decade. To date, immune checkpoint inhibitors (ICIs) of CTLA-4 and PD-1/PD-L1 represent the main class of immunotherapy. Blockade of CTLA-4 and PD-1/PD-L1 has shown remarkable efficacy in several specific types of cancers, however, a large subset of refractory patients presents poor responsiveness to ICB therapy; and the underlying mechanism remains elusive. Recently, numerous studies have revealed that metabolic reprogramming of tumor cells restrains immune responses by remodeling the tumor microenvironment (TME) with various products of metabolism, and combination therapies involving metabolic inhibitors and ICIs provide new approaches to cancer therapy. Nevertheless, a systematic summary is lacking regarding the manner by which different targetable metabolic pathways regulate immune checkpoints to overcome ICI resistance. Here, we demonstrate the generalized mechanism of targeting cancer metabolism at three crucial immune checkpoints (CTLA-4, PD-1, and PD-L1) to influence ICB therapy and propose potential combined immunotherapeutic strategies co-targeting tumor metabolic pathways and immune checkpoints.

Keywords

CTLA-4 / PD-1 / PD-L1 / immune checkpoint blockade (ICB) / metabolic reprogramming / combined tumor therapeutic strategies

References

[1] Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, Matory YL, Skibber JM, Shiloni E, Vetto JT, Seipp CA, Simpson C, Reichert CM. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med 1985; 313(23): 1485–1492

[2] Strander H, Einhorn S. Interferon therapy in neoplastic diseases. Philos Trans R Soc Lond B Biol Sci 1982; 299(1094): 113–117

[3] Einhorn S, Wasserman J, Lundell G, Blomgren H, Cedermark B, Jarstrand C, Petrini B, Strander H, Theve T, Ohman U. Treatment of patients with disseminated colorectal cancer with recombinant human alpha 2-interferon. Studies on the immune system. Int J Cancer 1984; 33(2): 251–256

[4] Limmer A, Sacher T, Alferink J, Kretschmar M, Schönrich G, Nichterlein T, Arnold B, Hämmerling GJ. Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment. Eur J Immunol 1998; 28(8): 2395–2406

[5] Wang C, Thudium KB, Han M, Wang XT, Huang H, Feingersh D, Garcia C, Wu Y, Kuhne M, Srinivasan M, Singh S, Wong S, Garner N, Leblanc H, Bunch RT, Blanset D, Selby MJ, Korman AJ. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2014; 2(9): 846–856

[6] Korman AJ, Garrett-Thomson SC, Lonberg N. The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov 2022; 21(7): 509–528

[7] Lonberg N, Korman AJ. Masterful antibodies: checkpoint blockade. Cancer Immunol Res 2017; 5(4): 275–281

[8] Schoenfeld AJ, Hellmann MD. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 2020; 37(4): 443–455

[9] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011; 144(5): 646–674

[10] Warburg O. On the origin of cancer cells. Science 1956; 123(3191): 309–314

[11] Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009; 324(5930): 1029–1033

[12] Dayton TL, Jacks T, Vander Heiden MG. PKM2, cancer metabolism, and the road ahead. EMBO Rep 2016; 17(12): 1721–1730

[13] AltmanBJStineZEDangCV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 2016; 16(12): 773 (Erratum for: Nat Rev Cancer 2016; 16(10): 619–634) doi:10.1038/nrc.2016.131

[14] Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol 2017; 24(9): 1161–1180

[15] DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene 2010; 29(3): 313–324

[16] Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 2011; 43(9): 869–874

[17] Snell K, Natsumeda Y, Eble JN, Glover JL, Weber G. Enzymic imbalance in serine metabolism in human colon carcinoma and rat sarcoma. Br J Cancer 1988; 57(1): 87–90

[18] Röhrig F, Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer 2016; 16(11): 732–749

[19] Walenta S, Mueller-Klieser WF. Lactate: mirror and motor of tumor malignancy. Semin Radiat Oncol 2004; 14(3): 267–274

[20] Certo M, Tsai CH, Pucino V, Ho PC, Mauro C. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat Rev Immunol 2021; 21(3): 151–161

[21] Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P. A new member of the immunoglobulin superfamily—CTLA-4. Nature 1987; 328(6127): 267–270

[22] Valk E, Rudd CE, Schneider H. CTLA-4 trafficking and surface expression. Trends Immunol 2008; 29(6): 272–279

[23] Rudd CE, Taylor A, Schneider H. CD28 and CTLA-4 coreceptor expression and signal transduction. Immunol Rev 2009; 229(1): 12–26

[24] Collins AV, Brodie DW, Gilbert RJ, Iaboni A, Manso-Sancho R, Walse B, Stuart DI, van der Merwe PA, Davis SJ. The interaction properties of costimulatory molecules revisited. Immunity 2002; 17(2): 201–210

[25] van der Merwe PA, Bodian DL, Daenke S, Linsley P, Davis SJ. CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J Exp Med 1997; 185(3): 393–404

[26] Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A, Yagita H, Tokunaga M, Saito T. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 2010; 33(3): 326–339

[27] Zhang H, Dai Z, Wu W, Wang Z, Zhang N, Zhang L, Zeng WJ, Liu Z, Cheng Q. Regulatory mechanisms of immune checkpoints PD-L1 and CTLA-4 in cancer. J Exp Clin Cancer Res 2021; 40(1): 184

[28] Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008; 26(1): 677–704

[29] Zhang J, Dang F, Ren J, Wei W. Biochemical aspects of PD-L1 regulation in cancer immunotherapy. Trends Biochem Sci 2018; 43(12): 1014–1032

[30] Dai X, Gao Y, Wei W. Post-translational regulations of PD-L1 and PD-1: mechanisms and opportunities for combined immunotherapy. Semin Cancer Biol 2022; 85: 246–252

[31] Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol 1927; 8(6): 519–530

[32] O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol 2016; 16(9): 553–565

[33] Buck MD, O’Sullivan D, Pearce EL. T cell metabolism drives immunity. J Exp Med 2015; 212(9): 1345–1360

[34] 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. Nat Commun 2015; 6(1): 6692

[35] Odorizzi PM, Pauken KE, Paley MA, Sharpe A, Wherry EJ. Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8⁺ T cells. J Exp Med 2015; 212(7): 1125–1137

[36] Chowdhury PS, Chamoto K, Kumar A, Honjo T. 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 2018; 6(11): 1375–1387

[37] Pokhrel RH, Acharya S, Ahn JH, Gu Y, Pandit M, Kim JO, Park YY, Kang B, Ko HJ, Chang JH. AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway. Mol Cancer 2021; 20(1): 133

[38] Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16(6): 769–777

[39] Zappasodi R, Serganova I, Cohen IJ, Maeda M, Shindo M, Senbabaoglu Y, Watson MJ, Leftin A, Maniyar R, Verma S, Lubin M, Ko M, Mane MM, Zhong H, Liu C, Ghosh A, Abu-Akeel M, Ackerstaff E, Koutcher JA, Ho PC, Delgoffe GM, Blasberg R, Wolchok JD, Merghoub T. CTLA-4 blockade drives loss of T_reg stability in glycolysis-low tumours. Nature 2021; 591(7851): 652–658

[40] Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012; 148(3): 399–408

[41] Synnestvedt K, Furuta GT, Comerford KM, Louis N, Karhausen J, Eltzschig HK, Hansen KR, Thompson LF, Colgan SP. Ecto-5′-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia. J Clin Invest 2002; 110(7): 993–1002

[42] Blay J, White TD, Hoskin DW. The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine. Cancer Res 1997; 57(13): 2602–2605

[43] Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 2017; 276(1): 121–144

[44] Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 2001; 414(6866): 916–920

[45] Sitkovsky MV, Ohta A. The ‘danger’ sensors that STOP the immune response: the A2 adenosine receptors?. Trends Immunol 2005; 26(6): 299–304

[46] Ohta A, Kini R, Ohta A, Subramanian M, Madasu M, Sitkovsky M. The development and immunosuppressive functions of CD4⁺CD25⁺FoxP3⁺ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway. Front Immunol 2012; 3: 190

[47] Allard B, Pommey S, Smyth MJ, Stagg J. Targeting CD73 enhances the antitumor activity of anti-PD-1 and anti-CTLA-4 mAbs. Clin Cancer Res 2013; 19(20): 5626–5635

[48] Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J, Liu L, Buggy JJ, McCaffery I, Miller RA. A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-(L)1 and anti-CTLA-4 in preclinical models. Cancer Immunol Res 2018; 6(10): 1136–1149

[49] Fong L, Hotson A, Powderly JD, Sznol M, Heist RS, Choueiri TK, George S, Hughes BGM, Hellmann MD, Shepard DR, Rini BI, Kummar S, Weise AM, Riese MJ, Markman B, Emens LA, Mahadevan D, Luke JJ, Laport G, Brody JD, Hernandez-Aya L, Bonomi P, Goldman JW, Berim L, Renouf DJ, Goodwin RA, Munneke B, Ho PY, Hsieh J, McCaffery I, Kwei L, Willingham SB, Miller RA. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov 2020; 10(1): 40–53

[50] Bjørgo E, Moltu K, Taskén K. Phosphodiesterases as targets for modulating T-cell responses. Handb Exp Pharmacol 2011; 204(204): 345–363

[51] Vendetti S, Riccomi A, Sacchi A, Gatta L, Pioli C, De Magistris MT. Cyclic adenosine 5′-monophosphate and calcium induce CD152 (CTLA-4) up-regulation in resting CD4⁺ T lymphocytes. J Immunol 2002; 169(11): 6231–6235

[52] Sitkovsky MV, Hatfield S, Abbott R, Belikoff B, Lukashev D, Ohta A. Hostile, hypoxia-A2-adenosinergic tumor biology as the next barrier to overcome for tumor immunologists. Cancer Immunol Res 2014; 2(7): 598–605

[53] Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E, Schreiber RD, Pearce EJ, Pearce EL. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162(6): 1229–1241

[54] Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, 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): 1239–1251

[55] Klein Geltink RI, Edwards-Hicks J, Apostolova P, O’Sullivan D, Sanin DE, Patterson AE, Puleston DJ, Ligthart NAM, Buescher JM, Grzes KM, Kabat AM, Stanczak M, Curtis JD, Hässler F, Uhl FM, Fabri M, Zeiser R, Pearce EJ, Pearce EL. Metabolic conditioning of CD8⁺ effector T cells for adoptive cell therapy. Nat Metab 2020; 2(8): 703–716

[56] Cerezo M, Rocchi S. Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy. Cell Death Dis 2020; 11(11): 964

[57] Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E. Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 2012; 131(3): 633–640

[58] Li M, Sun XH, Zhu XJ, Jin SG, Zeng ZJ, Zhou ZH, Yu Z, Gao YQ. HBcAg induces PD-1 upregulation on CD4⁺ T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients. Lab Invest 2012; 92(2): 295–304

[59] Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, Cline GW, Phillips AJ, Medzhitov R. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014; 513(7519): 559–563

[60] Bosticardo M, Ariotti S, Losana G, Bernabei P, Forni G, Novelli F. Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation. Eur J Immunol 2001; 31(9): 2829–2838

[61] Nagaraju K, Raben N, Villalba ML, Danning C, Loeffler LA, Lee E, Tresser N, Abati A, Fetsch P, Plotz PH. Costimulatory markers in muscle of patients with idiopathic inflammatory myopathies and in cultured muscle cells. Clin Immunol 1999; 92(2): 161–169

[62] Yu S, Zang W, Qiu Y, Liao L, Zheng X. Deubiquitinase OTUB2 exacerbates the progression of colorectal cancer by promoting PKM2 activity and glycolysis. Oncogene 2022; 41(1): 46–56

[63] Ji Y, Yang C, Tang Z, Yang Y, Tian Y, Yao H, Zhu X, Zhang Z, Ji J, Zheng X. Adenylate kinase hCINAP determines self-renewal of colorectal cancer stem cells by facilitating LDHA phosphorylation. Nat Commun 2017; 8(1): 15308

[64] Xu K, Yin N, Peng M, Stamatiades EG, Chhangawala S, Shyu A, Li P, Zhang X, Do MH, Capistrano KJ, Chou C, Leslie CS, Li MO. Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses. Immunity 2021; 54(5): 976–987.e7

[65] Li W, Xu M, Li Y, Huang Z, Zhou J, Zhao Q, Le K, Dong F, Wan C, Yi P. Comprehensive analysis of the association between tumor glycolysis and immune/inflammation function in breast cancer. J Transl Med 2020; 18(1): 92

[66] Han C, Ge M, Ho PC, Zhang L. Fueling T-cell antitumor immunity: amino acid metabolism revisited. Cancer Immunol Res 2021; 9(12): 1373–1382

[67] Prendergast GC, Malachowski WJ, Mondal A, Scherle P, Muller AJ. Indoleamine 2,3-dioxygenase and its therapeutic inhibition in cancer. Int Rev Cell Mol Biol 2018; 336: 175–203

[68] Liu M, Li Z, Yao W, Zeng X, Wang L, Cheng J, Ma B, Zhang R, Min W, Wang H. IDO inhibitor synergized with radiotherapy to delay tumor growth by reversing T cell exhaustion. Mol Med Rep 2020; 21(1): 445–453

[69] Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 2010; 185(6): 3190–3198

[70] Rohlman D, Punj S, Pennington J, Bradford S, Kerkvliet NI. Suppression of acute graft-versus-host response by TCDD is independent of the CTLA-4-IFN-γ-IDO pathway. Toxicol Sci 2013; 135(1): 81–90

[71] Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, Fiskesund R, Xie J, Liu J, Yin X, Jin X, Chen D, Tang K, Ma J, Zhang H, Yu J, Yan J, Liang H, Mo S, Cheng F, Zhou Y, Zhang H, Wang J, Li J, Chen Y, Cui B, Hu ZW, Cao X, Xiao-Feng Qin F, Huang B. Tumor-repopulating cells induce PD-1 expression in CD8⁺ T cells by transferring kynurenine and AhR activation. Cancer Cell 2018; 33(3): 480–494.e7

[72] Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV. c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 2009; 458(7239): 762–765

[73] Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 2010; 185(2): 1037–1044

[74] Wang W, Guo MN, Li N, Pang DQ, Wu JH. Glutamine deprivation impairs function of infiltrating CD8⁺ T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis. World J Gastrointest Oncol 2022; 14(6): 1124–1140

[75] Hu YM, Hsiung YC, Pai MH, Yeh SL. Glutamine administration in early or late septic phase downregulates lymphocyte PD-1/PD-L1 expression and the inflammatory response in mice with polymicrobial sepsis. JPEN J Parenter Enteral Nutr 2018; 42(3): 538–549

[76] Hopkins BD, Goncalves MD, Cantley LC. Insulin-PI3K signalling: an evolutionarily insulated metabolic driver of cancer. Nat Rev Endocrinol 2020; 16(5): 276–283

[77] Kraeuter AK, Guest PC, Sarnyai Z. Protocol for the use of the ketogenic diet in preclinical and clinical practice. Methods Mol Biol 2020; 2138: 83–98

[78] Jiang F, Luo F, Zeng N, Mao Y, Tang X, Wang J, Hu Y, Wu C. Characterization of fatty acid metabolism-related genes landscape for predicting prognosis and aiding immunotherapy in glioma patients. Front Immunol 2022; 13: 902143

[79] Ferrere G, Tidjani Alou M, Liu P, Goubet AG, Fidelle M, Kepp O, Durand S, Iebba V, Fluckiger A, Daillère R, Thelemaque C, Grajeda-Iglesias C, Alves Costa Silva C, Aprahamian F, Lefevre D, Zhao L, Ryffel B, Colomba E, Arnedos M, Drubay D, Rauber C, Raoult D, Asnicar F, Spector T, Segata N, Derosa L, Kroemer G, Zitvogel L. Ketogenic diet and ketone bodies enhance the anticancer effects of PD-1 blockade. JCI Insight 2021; 6(2): e145207

[80] Perry RJ, Wang Y, Cline GW, Rabin-Court A, Song JD, Dufour S, Zhang XM, Petersen KF, Shulman GI. Leptin mediates a glucose-fatty acid cycle to maintain glucose homeostasis in starvation. Cell 2018; 172(1–2): 234–248.e17

[81] Zhao S, Kusminski CM, Elmquist JK, Scherer PE. Leptin: less is more. Diabetes 2020; 69(5): 823–829

[82] Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, Mirsoian A, Minnar CM, Stoffel KM, Sturgill IR, Grossenbacher SK, Withers SS, Rebhun RB, Hartigan-O’Connor DJ, Méndez-Lagares G, Tarantal AF, Isseroff RR, Griffith TS, Schalper KA, Merleev A, Saha A, Maverakis E, Kelly K, Aljumaily R, Ibrahimi S, Mukherjee S, Machiorlatti M, Vesely SK, Longo DL, Blazar BR, Canter RJ, Murphy WJ, Monjazeb AM. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 2019; 25(1): 141–151

[83] Zech T, Ejsing CS, Gaus K, de Wet B, Shevchenko A, Simons K, Harder T. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J 2009; 28(5): 466–476

[84] Ma X, Bi E, Lu Y, Su P, Huang C, Liu L, Wang Q, Yang M, Kalady MF, Qian J, Zhang A, Gupte AA, Hamilton DJ, Zheng C, Yi Q. Cholesterol induces CD8⁺ T cell exhaustion in the tumor microenvironment. Cell Metab 2019; 30(1): 143–156.e5

[85] 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 CC, 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

[86] Barisano D, Frohman MA. Roles for phospholipase D1 in the tumor microenvironment. Adv Exp Med Biol 2020; 1259: 77–87

[87] Wolf A, Tanguy E, Wang Q, Gasman S, Vitale N. Phospholipase D and cancer metastasis: a focus on exosomes. Adv Biol Regul 2023; 87: 100924

[88] Mead KI, Zheng Y, Manzotti CN, Perry LC, Liu MK, Burke F, Powner DJ, Wakelam MJ, Sansom DM. Exocytosis of CTLA-4 is dependent on phospholipase D and ADP ribosylation factor-1 and stimulated during activation of regulatory T cells. J Immunol 2005; 174(8): 4803–4811

[89] Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999; 5(12): 1365–1369

[90] Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192(7): 1027–1034

[91] Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8(8): 793–800

[92] Akinleye A, Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics. J Hematol Oncol 2019; 12(1): 92

[93] Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017; 168(4): 707–723

[94] Guo D, Tong Y, Jiang X, Meng Y, Jiang H, Du L, Wu Q, Li S, Luo S, Li M, Xiao L, He H, He X, Yu Q, Fang J, Lu Z. Aerobic glycolysis promotes tumor immune evasion by hexokinase2-mediated phosphorylation of IκBα. Cell Metab 2022; 34(9): 1312–1324.e6

[95] Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci U S A 2004; 101(10): 3329–3335

[96] Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330(7503): 1304–1305

[97] Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, Li CW, Kim T, Chang SS, Lee HH, Hsu JL, 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. Mol Cell 2018; 71(4): 606–620.e7

[98] Vousden KH, Ryan KM. p53 and metabolism. Nat Rev Cancer 2009; 9(10): 691–700

[99] Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y, Araujo L, Carbone DP, Shilo K, Giri DK, Kelnar K, Martin D, Komaki R, Gomez DR, Krishnan S, Calin GA, Bader AG, Welsh JW. PDL1 Regulation by p53 via miR-34. J Natl Cancer Inst 2015; 108(1): djv303

[100] Oermann EK, Wu J, Guan KL, Xiong Y. Alterations of metabolic genes and metabolites in cancer. Semin Cell Dev Biol 2012; 23(4): 370–380

[101] Tuo Z, Zong Y, Li J, Xiao G, Zhang F, Li G, Wang S, Lv Y, Xia J, Liu J. PD-L1 regulation by SDH5 via β-catenin/ZEB1 signaling. Oncoimmunology 2019; 8(12): 1655361

[102] Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA, Zhang X, Yi X, Dwyer D, Lin W, Diao L, Wang J, Roybal J, Patel M, Ungewiss C, Peng D, Antonia S, Mediavilla-Varela M, Robertson G, Suraokar M, Welsh JW, Erez B, Wistuba II, Chen L, Peng D, Wang S, Ullrich SE, Heymach JV, Kurie JM, Qin FX. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5(1): 5241

[103] Núñez FJ, Mendez FM, Kadiyala P, Alghamri MS, Savelieff MG, Garcia-Fabiani MB, Haase S, Koschmann C, Calinescu AA, Kamran N, Saxena M, Patel R, Carney S, Guo MZ, Edwards M, Ljungman M, Qin T, Sartor MA, Tagett R, Venneti S, Brosnan-Cashman J, Meeker A, Gorbunova V, Zhao L, Kremer DM, Zhang L, Lyssiotis CA, Jones L, Herting CJ, Ross JL, Hambardzumyan D, Hervey-Jumper S, Figueroa ME, Lowenstein PR, Castro MG. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Sci Transl Med 2019; 11(479): eaaq1427

[104] Mu L, Long Y, Yang C, Jin L, Tao H, Ge H, Chang YE, Karachi A, Kubilis PS, De Leon G, Qi J, Sayour EJ, Mitchell DA, Lin Z, Huang J. The IDH1 mutation-induced oncometabolite, 2-hydroxyglutarate, may affect DNA methylation and expression of PD-L1 in gliomas. Front Mol Neurosci 2018; 11: 82

[105] Kadiyala P, Carney SV, Gauss JC, Garcia-Fabiani MB, Haase S, Alghamri MS, Núñez FJ, Liu Y, Yu M, Taher A, Nunez FM, Li D, Edwards MB, Kleer CG, Appelman H, Sun Y, Zhao L, Moon JJ, Schwendeman A, Lowenstein PR, Castro MG. Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice. J Clin Invest 2021; 131(4): e139542

[106] Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, Shu Y. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer 2019; 18(1): 157

[107] Palsson-McDermott EM, Dyck L, Zasłona Z, Menon D, McGettrick AF, Mills KHG, O’Neill LA. Pyruvate kinase M2 is required for the expression of the immune checkpoint PD-L1 in immune cells and tumors. Front Immunol 2017; 8: 1300

[108] Xia Q, Jia J, Hu C, Lu J, Li J, Xu H, Fang J, Feng D, Wang L, Chen Y. Tumor-associated macrophages promote PD-L1 expression in tumor cells by regulating PKM2 nuclear translocation in pancreatic ductal adenocarcinoma. Oncogene 2022; 41(6): 865–877

[109] Huang Y, Lin D, Taniguchi CM. Hypoxia inducible factor (HIF) in the tumor microenvironment: friend or foe?. Sci China Life Sci 2017; 60(10): 1114–1124

[110] Kuo P, Le QT. Galectin-1 links tumor hypoxia and radiotherapy. Glycobiology 2014; 24(10): 921–925

[111] Guda MR, Tsung AJ, Asuthkar S, Velpula KK. Galectin-1 activates carbonic anhydrase IX and modulates glioma metabolism. Cell Death Dis 2022; 13(6): 574

[112] Nambiar DK, Aguilera T, Cao H, Kwok S, Kong C, Bloomstein J, Wang Z, Rangan VS, Jiang D, von Eyben R, Liang R, Agarwal S, Colevas AD, Korman A, Allen CT, Uppaluri R, Koong AC, Giaccia A, Le QT. Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J Clin Invest 2019; 129(12): 5553–5567

[113] Vuong L, Kouverianou E, Rooney CM, McHugh BJ, Howie SEM, Gregory CD, Forbes SJ, Henderson NC, Zetterberg FR, Nilsson UJ, Leffler H, Ford P, Pedersen A, Gravelle L, Tantawi S, Schambye H, Sethi T, MacKinnon AC. An orally active galectin-3 antagonist inhibits lung adenocarcinoma growth and augments response to PD-L1 blockade. Cancer Res 2019; 79(7): 1480–1492

[114] Hirschhaeuser F, Sattler UG, Mueller-Klieser W. Lactate: a metabolic key player in cancer. Cancer Res 2011; 71(22): 6921–6925

[115] Feng J, Yang H, Zhang Y, Wei H, Zhu Z, Zhu B, Yang M, Cao W, Wang L, Wu Z. Tumor cell-derived lactate induces TAZ-dependent upregulation of PD-L1 through GPR81 in human lung cancer cells. Oncogene 2017; 36(42): 5829–5839

[116] Lv H, Lv G, Chen C, Zong Q, Jiang G, Ye D, Cui X, He Y, Xiang W, Han Q, Tang L, Yang W, Wang H. NAD⁺ metabolism maintains inducible PD-L1 expression to drive tumor immune evasion. Cell Metab 2021; 33(1): 110–127.e5

[117] Yao H, Lan J, Li C, Shi H, Brosseau JP, Wang H, Lu H, Fang C, Zhang Y, Liang L, Zhou X, Wang C, Xue Y, Cui Y, Xu J. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng 2019; 3(4): 306–317

[118] Nakamura T, Sato T, Endo R, Sasaki S, Takahashi N, Sato Y, Hyodo M, Hayakawa Y, Harashima H. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. J Immunother Cancer 2021; 9(7): e002852

[119] Yang Y, Hsu JM, Sun L, Chan LC, Li CW, Hsu JL, Wei Y, Xia W, Hou J, Qiu Y, Hung MC. Palmitoylation stabilizes PD-L1 to promote breast tumor growth. Cell Res 2019; 29(1): 83–86

[120] Li X, Qian X, Lu Z. Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy. Autophagy 2017; 13(10): 1790–1791

[121] Bradshaw PC. Acetyl-CoA metabolism and histone acetylation in the regulation of aging and lifespan. Antioxidants (Basel) 2021; 10(4): 572

[122] Gao Y, Nihira NT, Bu X, Chu C, Zhang J, Kolodziejczyk A, Fan Y, Chan NT, Ma L, Liu J, Wang D, Dai X, Liu H, Ono M, Nakanishi A, Inuzuka H, North BJ, Huang YH, Sharma S, Geng Y, Xu W, Liu XS, Li L, Miki Y, Sicinski P, Freeman GJ, Wei W. Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy. Nat Cell Biol 2020; 22(9): 1064–1075

[123] Feng X, Zhang L, Xu S, Shen AZ. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog Lipid Res 2020; 77: 101006

[124] Guertin DA, Wellen KE. Acetyl-CoA metabolism in cancer. Nat Rev Cancer 2023; 23(3): 156–172

[125] Gu L, Zhu Y, Lin X, Lu B, Zhou X, Zhou F, Zhao Q, Prochownik EV, Li Y. The IKKβ-USP30-ACLY axis controls lipogenesis and tumorigenesis. Hepatology 2021; 73(1): 160–174

[126] Shahid M, Kim M, Jin P, Zhou B, Wang Y, Yang W, You S, Kim J. S-palmitoylation as a functional regulator of proteins associated with cisplatin resistance in bladder cancer. Int J Biol Sci 2020; 16(14): 2490–2505

[127] Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z. Lipid metabolism and cancer. J Exp Med 2021; 218(1): e20201606

[128] Li XJ, Li QL, Ju LG, Zhao C, Zhao LS, Du JW, Wang Y, Zheng L, Song BL, Li LY, Li L, Wu M. Deficiency of histone methyltransferase SET domain-containing 2 in liver leads to abnormal lipid metabolism and HCC. Hepatology 2021; 73(5): 1797–1815

[129] Green MR, Rodig S, Juszczynski P, Ouyang J, Sinha P, O’Donnell E, Neuberg D, Shipp MA. Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy. Clin Cancer Res 2012; 18(6): 1611–1618

[130] Wang Q, Cao Y, Shen L, Xiao T, Cao R, Wei S, Tang M, Du L, Wu H, Wu B, Yu Y, Wang S, Wen M, OuYang B. Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs. Sci Adv 2022; 8(34): eabq4722

[131] Wang JJ, Siu MK, Jiang YX, Leung TH, Chan DW, Wang HG, Ngan HY, Chan KK. A combination of glutaminase inhibitor 968 and PD-L1 blockade boosts the immune response against ovarian cancer. Biomolecules 2021; 11(12): 1749

[132] Ma G, Liang Y, Chen Y, Wang L, Li D, Liang Z, Wang X, Tian D, Yang X, Niu H. Glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer. Mol Cancer Res 2020; 18(2): 324–339

[133] Yu Y, Liang Y, Li D, Wang L, Liang Z, Chen Y, Ma G, Wu H, Jiao W, Niu H. Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment. Cell Death Discov 2021; 7(1): 15

[134] Son J, Lyssiotis CA, Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC, Kimmelman AC. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013; 496(7443): 101–105

[135] Hashimoto S, Furukawa S, Hashimoto A, Tsutaho A, Fukao A, Sakamura Y, Parajuli G, Onodera Y, Otsuka Y, Handa H, Oikawa T, Hata S, Nishikawa Y, Mizukami Y, Kodama Y, Murakami M, Fujiwara T, Hirano S, Sabe H. ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer. Proc Natl Acad Sci U S A 2019; 116(35): 17450–17459

[136] Bassi MT, Gasol E, Manzoni M, Pineda M, Riboni M, Martín R, Zorzano A, Borsani G, Palacín M. Identification and characterisation of human xCT that co-expresses, with 4F2 heavy chain, the amino acid transport activity system x_c^–. Pflugers Arch 2001; 442(2): 286–296

[137] Liu N, Zhang J, Yin M, Liu H, Zhang X, Li J, Yan B, Guo Y, Zhou J, Tao J, Hu S, Chen X, Peng C. Inhibition of xCT suppresses the efficacy of anti-PD-1/L1 melanoma treatment through exosomal PD-L1-induced macrophage M2 polarization. Mol Ther 2021; 29(7): 2321–2334

[138] Arensman MD, Yang XS, Leahy DM, Toral-Barza L, Mileski M, Rosfjord EC, Wang F, Deng S, Myers JS, Abraham RT, Eng CH. Cystine-glutamate antiporter xCT deficiency suppresses tumor growth while preserving antitumor immunity. Proc Natl Acad Sci U S A 2019; 116(19): 9533–9542

[139] Faubert B, Vincent EE, Griss T, Samborska B, Izreig S, Svensson RU, Mamer OA, Avizonis D, Shackelford DB, Shaw RJ, Jones RG. Loss of the tumor suppressor LKB1 promotes metabolic reprogramming of cancer cells via HIF-1α. Proc Natl Acad Sci U S A 2014; 111(7): 2554–2559

[140] Liu Z, Li S, Zeng J, Zhou X, Li H, Liu X, Li F, Jiang B, Zhao M, Ma T. LKB1 inhibits intrahepatic cholangiocarcinoma by repressing the transcriptional activity of the immune checkpoint PD-L1. Life Sci 2020; 257: 118068

[141] Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab 2012; 15(1): 110–121

[142] Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gütgemann I, Eilers M, Felsher DW. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 2016; 352(6282): 227–231

[143] Di Marcantonio D, Martinez E, Kanefsky JS, Huhn JM, Gabbasov R, Gupta A, Krais JJ, Peri S, Tan Y, Skorski T, Dorrance A, Garzon R, Goldman AR, Tang HY, Johnson N, Sykes SM. ATF3 coordinates serine and nucleotide metabolism to drive cell cycle progression in acute myeloid leukemia. Mol Cell 2021; 81(13): 2752–2764.e6

[144] Liu H, Kuang X, Zhang Y, Ye Y, Li J, Liang L, Xie Z, Weng L, Guo J, Li H, Ma F, Chen X, Zhao S, Su J, Yang N, Fang F, Xie Y, Tao J, Zhang J, Chen M, Peng C, Sun L, Zhang X, Liu J, Han L, Xu X, Hung MC, Chen X. ADORA1 inhibition promotes tumor immune evasion by regulating the ATF3-PD-L1 axis. Cancer Cell 2020; 37(3): 324–339.e8

[145] Kuo MT, Savaraj N, Feun LG. Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes. Oncotarget 2010; 1(4): 246–251

[146] Carpentier J, Pavlyk I, Mukherjee U, Hall PE, Szlosarek PW. Arginine deprivation in SCLC: mechanisms and perspectives for therapy. Lung Cancer (Auckl) 2022; 13: 53–66

[147] He X, Lin H, Yuan L, Li B. Combination therapy with L-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice. Cancer Biol Ther 2017; 18(2): 94–100

[148] Martí i Líndez AA, Dunand-Sauthier I, Conti M, Gobet F, Núñez N, Hannich JT, Riezman H, Geiger R, Piersigilli A, Hahn K, Lemeille S, Becher B, De Smedt T, Hugues S, Reith W. Mitochondrial arginase-2 is a cell-autonomous regulator of CD8⁺ T cell function and antitumor efficacy. JCI Insight 2019; 4(24): e132975

[149] Maffei ME. 5-hydroxytryptophan (5-HTP): natural occurrence, analysis, biosynthesis, biotechnology, physiology and toxicology. Int J Mol Sci 2021; 22(1): 181

[150] Huang J, Wang X, Li B, Shen S, Wang R, Tao H, Hu J, Yu J, Jiang H, Chen K, Luo C, Dang Y, Zhang Y. L-5-hydroxytryptophan promotes antitumor immunity by inhibiting PD-L1 inducible expression. J Immunother Cancer 2022; 10(6): e003957

[151] Daneshmandi S, Wegiel B, Seth P. Blockade of lactate dehydrogenase-A (LDH-A) improves efficacy of anti-programmed cell death-1 (PD-1) therapy in melanoma. Cancers (Basel) 2019; 11(4): 450

[152] Hu R, Zhou B, Chen Z, Chen S, Chen N, Shen L, Xiao H, Zheng Y. PRMT5 inhibition promotes PD-L1 expression and immuno-resistance in lung cancer. Front Immunol 2022; 12: 722188

[153] Gao W, Zhang X, Yang W, Dou D, Zhang H, Tang Y, Zhong W, Meng J, Bai Y, Liu Y, Yang L, Chen S, Liu H, Yang C, Sun T. Prim-O-glucosylcimifugin enhances the antitumour effect of PD-1 inhibition by targeting myeloid-derived suppressor cells. J Immunother Cancer 2019; 7(1): 231

[154] Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 2017; 5(1): 9–16

[155] He L. Metformin and systemic metabolism. Trends Pharmacol Sci 2020; 41(11): 868–881

[156] Huang MY, Jiang XM, Xu YL, Yuan LW, Chen YC, Cui G, Huang RY, Liu B, Wang Y, Chen X, Lu JJ. Platycodin D triggers the extracellular release of programed death ligand-1 in lung cancer cells. Food Chem Toxicol 2019; 131: 110537

[157] Huang J, Chen G, Wang J, Liu S, Su J. Platycodin D regulates high glucose-induced ferroptosis of HK-2 cells through glutathione peroxidase 4 (GPX4). Bioengineered 2022; 13(3): 6627–6637

[158] Kawauchi K, Araki K, Tobiume K, Tanaka N. p53 regulates glucose metabolism through an IKK-NF-kappaB pathway and inhibits cell transformation. Nat Cell Biol 2008; 10(5): 611–618

[159] Li N, Liu Q, Han Y, Pei S, Cheng B, Xu J, Miao X, Pan Q, Wang H, Guo J, Wang X, Zhang G, Lian Y, Zhang W, Zang Y, Tan M, Li Q, Wang X, Xiao Y, Hu G, Jiang J, Huang H, Qin J. ARID1A loss induces polymorphonuclear myeloid-derived suppressor cell chemotaxis and promotes prostate cancer progression. Nat Commun 2022; 13(1): 7281

[160] Chen X, Xun K, Chen L, Wang Y. TNF-alpha, a potent lipid metabolism regulator. Cell Biochem Funct 2009; 27(7): 407–416

[161] Quandt D, Jasinski-Bergner S, Müller U, Schulze B, Seliger B. Synergistic effects of IL-4 and TNFα on the induction of B7-H1 in renal cell carcinoma cells inhibiting allogeneic T cell proliferation. J Transl Med 2014; 12(1): 151

[162] Vredevoogd DW, Kuilman T, Ligtenberg MA, Boshuizen J, Stecker KE, de Bruijn B, Krijgsman O, Huang X, Kenski JCN, Lacroix R, Mezzadra R, Gomez-Eerland R, Yildiz M, Dagidir I, Apriamashvili G, Zandhuis N, van der Noort V, Visser NL, Blank CU, Altelaar M, Schumacher TN, Peeper DS. Augmenting immunotherapy impact by lowering tumor TNF cytotoxicity threshold. Cell 2019; 178(3): 585–599.e15

[163] Wee P, Wang Z. Epidermal growth factor receptor cell proliferation signaling pathways. Cancers (Basel) 2017; 9(5): 52

[164] Jeon M, Chauhan KM, Szeto GL, Kyoung M, An S. Subcellular regulation of glucose metabolism through multienzyme glucosome assemblies by EGF-ERK1/2 signaling pathways. J Biol Chem 2022; 298(3): 101675

[165] Horita H, Law A, Hong S, Middleton K. Identifying regulatory posttranslational modifications of PD-L1: a focus on monoubiquitinaton. Neoplasia 2017; 19(4): 346–353

[166] Hsu PC, Jablons DM, Yang CT, You L. Epidermal growth factor receptor (EGFR) pathway, yes-associated protein (YAP) and the regulation of programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC). Int J Mol Sci 2019; 20(15): 3821

[167] Quan Z, Yang Y, Zheng H, Zhan Y, Luo J, Ning Y, Fan S. Clinical implications of the interaction between PD-1/PD-L1 and PI3K/AKT/mTOR pathway in progression and treatment of non-small cell lung cancer. J Cancer 2022; 13(13): 3434–3443

[168] Zhang N, Zeng Y, Du W, Zhu J, Shen D, Liu Z, Huang JA. The EGFR pathway is involved in the regulation of PD-L1 expression via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated non-small cell lung cancer. Int J Oncol 2016; 49(4): 1360–1368

[169] Li YJ, Zhang C, Martincuks A, Herrmann A, Yu H. STAT proteins in cancer: orchestration of metabolism. Nat Rev Cancer 2023; 23(3): 115–134

[170] Gao Y, Yang J, Cai Y, Fu S, Zhang N, Fu X, Li L. IFN-γ-mediated inhibition of lung cancer correlates with PD-L1 expression and is regulated by PI3K-AKT signaling. Int J Cancer 2018; 143(4): 931–943

[171] Stutvoet TS, Kol A, de Vries EG, de Bruyn M, Fehrmann RS, Terwisscha van Scheltinga AG, de Jong S. MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells. J Pathol 2019; 249(1): 52–64

[172] Leone RD, Zhao L, Englert JM, Sun IM, Oh MH, Sun IH, Arwood ML, Bettencourt IA, Patel CH, Wen J, Tam A, Blosser RL, Prchalova E, Alt J, Rais R, Slusher BS, Powell JD. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019; 366(6468): 1013–1021

[173] 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.e9

[174] Olson B, Li Y, Lin Y, Liu ET, Patnaik A. Mouse models for cancer immunotherapy research. Cancer Discov 2018; 8(11): 1358–1365

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82130081 and 32270756), the National Key R&D Program of China (No. 2022YFA1302803), and the Beijing Natural Science Foundation (No. 5212008).

Compliance with ethics guidelines

Conflict of interest Liming Liao, Huilin Xu, Yuhan Zhao, and Xiaofeng Zheng declare that they have no conflicts of interest.

This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2023 Higher Education Press