REFERENCES
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252-64.
3. Chen L, Han X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J Clin Invest 2015;125:3384-91.
4. Morad G, Helmink BA, Sharma P, Wargo JA. Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 2021;184:5309-37.
5. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol 1927;8:519-30.
7. Pavlova NN, Zhu J, Thompson CB. The hallmarks of cancer metabolism: still emerging. Cell Metab 2022;34:355-77.
9. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018;24:541-50.
10. Roy DG, Kaymak I, Williams KS, Ma EH, Jones RG. Immunometabolism in the tumor microenvironment. Annu Rev Cancer Biol 2021;5:137-59.
11. Brown TP, Ganapathy V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon. Pharmacol Ther 2020;206:107451.
12. Halestrap AP, Price NT. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. Biochem J 1999;343:281-99.
13. Halestrap AP. The SLC16 gene family - structure, role and regulation in health and disease. Mol Aspects Med 2013;34:337-49.
14. Sandforth L, Ammar N, Dinges LA, et al. Impact of the monocarboxylate transporter-1 (MCT1)-mediated cellular import of lactate on stemness properties of human pancreatic adenocarcinoma cells †. Cancers 2020;12:581.
15. Longhitano L, Forte S, Orlando L, et al. The crosstalk between GPR81/IGFBP6 promotes breast cancer progression by modulating lactate metabolism and oxidative stress. Antioxidants 2022;11:275.
16. Boedtkjer E, Pedersen SF. The acidic tumor microenvironment as a driver of cancer. Annu Rev Physiol 2020;82:103-26.
17. Notarangelo G, Spinelli JB, Perez EM, et al. Oncometabolite D-2HG alters T cell metabolism to impair CD8+ T cell function. Science 2022;377:1519-29.
18. Hermans D, Gautam S, García-Cañaveras JC, et al. Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity. Proc Natl Acad Sci U S A 2020;117:6047-55.
19. Rostamian H, Khakpoor-Koosheh M, Jafarzadeh L, et al. Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions. BMC Cancer 2022;22:39.
20. Franchina DG, Dostert C, Brenner D. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol 2018;39:489-502.
21. Fischer K, Hoffmann P, Voelkl S, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109:3812-9.
22. Brand A, Singer K, Koehl GE, et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 2016;24:657-71.
23. Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 2005;5:472-84.
24. Ping W, Senyan H, Li G, Yan C, Long L. Increased lactate in gastric cancer tumor-infiltrating lymphocytes is related to impaired T cell function due to miR-34a deregulated lactate dehydrogenase A. Cell Physiol Biochem 2018;49:828-36.
25. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol 2015;36:265-76.
26. Kaymak I, Luda KM, Duimstra LR, et al. Carbon source availability drives nutrient utilization in CD8+ T cells. Cell Metab 2022;34:1298-311.e6.
27. Hui S, Ghergurovich JM, Morscher RJ, et al. Glucose feeds the TCA cycle via circulating lactate. Nature 2017;551:115-8.
28. Faubert B, Li KY, Cai L, et al. Lactate metabolism in human lung tumors. Cell 2017;171:358-71.e9.
29. Quinn WJ 3rd, Jiao J, TeSlaa T, et al. Lactate limits T cell proliferation via the NAD(H) redox state. Cell Rep 2020;33:108500.
30. Xia H, Wang W, Crespo J, et al. Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity. Sci Immunol 2017;2:eaan4631.
31. Elia I, Rowe JH, Johnson S, et al. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells. Cell Metab 2022;34:1137-50.e6.
32. Angelin A, Gil-de-Gómez L, Dahiya S, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 2017;25:1282-93.e7.
33. Watson MJ, Vignali PDA, Mullett SJ, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 2021;591:645-51.
34. Stone SC, Rossetti RAM, Alvarez KLF, et al. Lactate secreted by cervical cancer cells modulates macrophage phenotype. J Leukoc Biol 2019;105:1041-54.
35. Kelderman S, Heemskerk B, van Tinteren H, et al. Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer Immunol Immunother 2014;63:449-58.
36. Nosrati A, Tsai KK, Goldinger SM, et al. Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer 2017;116:1141-7.
37. Zhang Z, Li Y, Yan X, et al. Pretreatment lactate dehydrogenase may predict outcome of advanced non small-cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Cancer Med 2019;8:1467-73.
38. Schouwenburg MG, Suijkerbuijk KPM, Koornstra RHT, et al. Switching to immune checkpoint inhibitors upon response to targeted therapy; the road to long-term survival in advanced melanoma patients with highly elevated serum LDH? Cancer 2019;11:1940.
39. Wang X, Zhang B, Chen X, et al. Lactate dehydrogenase and baseline markers associated with clinical outcomes of advanced esophageal squamous cell carcinoma patients treated with camrelizumab (SHR-1210), a novel anti-PD-1 antibody. Thorac Cancer 2019;10:1395-401.
40. Yin TT, Huang MX, Wang F, et al. Lactate score predicts survival, immune cell infiltration and response to immunotherapy in breast cancer. Front Genet 2022;13:943849.
41. Renner K, Bruss C, Schnell A, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep 2019;29:135-50.e9.
42. Li N, Kang Y, Wang L, et al. ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment. Proc Natl Acad Sci U S A 2020;117:20159-70.
43. Kumagai S, Koyama S, Itahashi K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer Cell 2022;40:201-18.e9.
44. Stransky N, Huber SM. Comment on Chen et al. Dual blockade of lactate/GPR81 and PD-1/PD-L1 pathways enhances the anti-tumor effects of metformin. Biomolecules 2021, 11, 1373. Biomolecules 2022;12:573.
45. Feng Q, Liu Z, Yu X, et al. Lactate increases stemness of CD8 + T cells to augment anti-tumor immunity. Nat Commun 2022;13:4981.
46. Kaczmarek E, Koziak K, Sévigny J, et al. Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 1996;271:33116-22.
47. Zimmermann H. 5'-nucleotidase: molecular structure and functional aspects. Biochem J 1992;285:345-65.
48. Horenstein AL, Chillemi A, Zaccarello G, et al. A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. Oncoimmunology 2013;2:e26246.
49. Campos-Contreras ADR, Díaz-Muñoz M, Vázquez-Cuevas FG. Purinergic signaling in the hallmarks of cancer. Cells 2020;9:1612.
50. Allard B, Longhi MS, Robson SC, Stagg J. The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 2017;276:121-44.
51. Ferretti E, Horenstein AL, Canzonetta C, Costa F, Morandi F. Canonical and non-canonical adenosinergic pathways. Immunol Lett 2019;205:25-30.
52. Allard B, Allard D, Buisseret L, Stagg J. Publisher correction: the adenosine pathway in immuno-oncology. Nat Rev Clin Oncol 2020;17:650.
53. Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth. Oncogene 2017;36:293-303.
54. Pellegatti P, Raffaghello L, Bianchi G, Piccardi F, Pistoia V, Di Virgilio F. Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase. PLoS One 2008;3:e2599.
55. Mora-García ML, Ávila-Ibarra LR, García-Rocha R, et al. Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway. Cell Immunol 2017;320:46-55.
56. Sundström P, Stenstad H, Langenes V, et al. Regulatory T cells from colon cancer patients inhibit effector T-cell migration through an adenosine-dependent mechanism. Cancer Immunol Res 2016;4:183-93.
57. Shi L, Feng M, Du S, et al. Adenosine generated by regulatory T Cells induces CD8+ T cell exhaustion in gastric cancer through A2aR pathway. Biomed Res Int 2019;2019:4093214.
58. Maj T, Wang W, Crespo J, et al. Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor. Nat Immunol 2017;18:1332-41.
59. Giatromanolaki A, Kouroupi M, Pouliliou S, et al. Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways. Life Sci 2020;259:118389.
60. Vignali PDA, DePeaux K, Watson MJ, et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat Immunol 2023;24:267-79.
61. 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.
62. Torres-Pineda DB, Mora-García ML, García-Rocha R, et al. Adenosine augments the production of IL-10 in cervical cancer cells through interaction with the A2B adenosine receptor, resulting in protection against the activity of cytotoxic T cells. Cytokine 2020;130:155082.
63. King RJ, Shukla SK, He C, et al. CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis. Oncogene 2022;41:971-82.
64. Ludwig N, Yerneni SS, Azambuja JH, et al. Tumor-derived exosomes promote angiogenesis via adenosine A2B receptor signaling. Angiogenesis 2020;23:599-610.
65. Ploeg EM, Ke X, Britsch I, et al. Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesicles. Cancer Lett 2021;521:109-18.
66. Morandi F, Marimpietri D, Horenstein AL, Corrias MV, Malavasi F. Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells. Oncoimmunology 2019;8:e1574198.
67. Clayton A, Al-Taei S, Webber J, Mason MD, Tabi Z. Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production. J Immunol 2011;187:676-83.
68. Chimote AA, Balajthy A, Arnold MJ, et al. A defect in KCa3.1 channel activity limits the ability of CD8+ T cells from cancer patients to infiltrate an adenosine-rich microenvironment. Sci Signal 2018;11:eaaq1616.
69. Chimote AA, Hajdu P, Kucher V, et al. Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells. J Immunol 2013;191:6273-80.
70. Feske S, Skolnik EY, Prakriya M. Ion channels and transporters in lymphocyte function and immunity. Nat Rev Immunol 2012;12:532-47.
71. Newton HS, Gawali VS, Chimote AA, et al. PD1 blockade enhances K+ channel activity, Ca2+ signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer. J Immunother Cancer 2020;8:e000844.
72. Deaglio S, Dwyer KM, Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 2007;204:1257-65.
73. Mandapathil M, Szczepanski MJ, Szajnik M, et al. Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res 2009;15:6348-57.
74. Koyas A, Tucer S, Kayhan M, Savas AC, Akdemir I, Cekic C. Interleukin-7 protects CD8+ T cells from adenosine-mediated immunosuppression. Sci Signal 2021;14:eabb1269.
75. Cekic C, Linden J. Adenosine A2A receptors intrinsically regulate CD8+ T cells in the tumor microenvironment. Cancer Res 2014;74:7239-49.
76. Huang S, Apasov S, Koshiba M, Sitkovsky M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 1997;90:1600-10.
77. Ohta A, Gorelik E, Prasad SJ, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 2006;103:13132-7.
78. Kjaergaard J, Hatfield S, Jones G, Ohta A, Sitkovsky M. A2A adenosine receptor gene deletion or synthetic A2A antagonist liberate tumor-reactive CD8+ T cells from tumor-induced immunosuppression. J Immunol 2018;201:782-91.
79. Newton HS, Chimote AA, Arnold MJ, Wise-Draper TM, Conforti L. Targeted knockdown of the adenosine A2A receptor by lipid NPs rescues the chemotaxis of head and neck cancer memory T cells. Mol Ther Methods Clin Dev 2021;21:133-43.
80. Ma SR, Deng WW, Liu JF, et al. Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma. Mol Cancer 2017;16:99.
81. Ohta A, Ohta A, Madasu M, et al. A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments1. J Immunol 2009;183:5487-93.
83. Sidders B, Zhang P, Goodwin K, et al. Adenosine signaling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response. Clin Cancer Res 2020;26:2176-87.
84. Fong L, Hotson A, Powderly JD, et al. Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer. Cancer Discov 2020;10:40-53.
85. Bai Y, Zhang X, Zheng J, Liu Z, Yang Z, Zhang X. Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist. J Exp Clin Cancer Res 2022;41:302.
86. Buisseret L, Rottey S, De Bono JS, et al. Phase 1 trial of the adenosine A2A receptor antagonist inupadenant (EOS-850): update on tolerability, and antitumor activity potentially associated with the expression of the A2A receptor within the tumor. J Clin Oncol 2021;39:2562.
87. Lu JC, Zhang PF, Huang XY, et al. Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma. J Hematol Oncol 2021;14:200.
88. Powderly J, Bendell J, Carneiro B, et al. 1073TiP A phase I, first-in-human, multicenter, open-label, dose-escalation study of IPH5201 as monotherapy or in combination with durvalumab ± oleclumab in advanced solid tumours. Ann Oncol 2020;31:S728-9.
89. Pharma I. IPH5201 and durvalumab in patients with resectable non-small cell lung cancer (MATISSE). Available from: https://clinicaltrials.gov/study/NCT05742607. [Last accessed on 30 Aug 2023].
90. Paturel C, Anceriz N, Eyles J, et al. 190P Combination of IPH5201, a blocking antibody targeting the CD39 immunosuppressive pathway, with durvalumab and chemotherapies: preclinical rationale. Immuno-Oncol Technol 2022;16:100302.
91. Wainberg Z, Kang YK, Lee KW, et al. Abstract CT015: safety and efficacy of TTX-030, an anti-CD39 antibody, in combination with chemoimmunotherapy for the first line treatment of locally advanced or metastatic gastric/GEJ cancer. Cancer Res 2022;82:CT015.
92. Bendell J, LoRusso P, Overman M, et al. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors. Cancer Immunol Immunother 2023;72:2443-58.
93. Herbst RS, Majem M, Barlesi F, et al. COAST: an open-label, phase II, Multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non-small-cell lung cancer. J Clin Oncol 2022;40:3383-93.
94. Yu W, Sun J, Wang X, et al. Boosting cancer immunotherapy via the convenient A2AR inhibition using a tunable nanocatalyst with light-enhanced activity. Adv Mater 2022;34:2106967.
95. Wu L, Xie W, Li Y, et al. Biomimetic nanocarriers guide extracellular ATP homeostasis to remodel energy metabolism for activating innate and adaptive immunity system. Adv Sci 2022;9:2105376.
96. Mao C, Yeh S, Fu J, et al. Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression. Sci Transl Med 2022;14:eabh1261.
97. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021;22:119-41.
98. Xie N, Zhang L, Gao W, et al. NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther 2020;5:227.
99. Dwivedi S, Rendón-Huerta EP, Ortiz-Navarrete V, Montaño LF. CD38 and regulation of the immune response cells in cancer. J Oncol 2021;2021:6630295.
100. Navas LE, Carnero A. NAD+ metabolism, stemness, the immune response, and cancer. Signal Transduct Target Ther 2021;6:2.
101. Yaku K, Okabe K, Hikosaka K, Nakagawa T. NAD metabolism in cancer therapeutics. Front Oncol 2018;8:622.
102. Liu HY, Wang FH, Liang JM, et al. Targeting NAD metabolism regulates extracellular adenosine levels to improve the cytotoxicity of CD8+ effector T cells in the tumor microenvironment of gastric cancer. J Cancer Res Clin Oncol 2023;149:2743-56.
103. Wang Y, Wang F, Wang L, et al. NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells. Cell Rep 2021;36:109516.
104. Gerner RR, Macheiner S, Reider S, et al. Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity. Leukemia 2020;34:1885-97.
105. Aswad F, Kawamura H, Dennert G. High sensitivity of CD4+CD25+ regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors. J Immunol 2005;175:3075-83.
106. Hubert S, Rissiek B, Klages K, et al. Extracellular NAD+ shapes the Foxp3+ regulatory T cell compartment through the ART2-P2X7 pathway. J Exp Med 2010;207:2561-8.
107. Wei Y, Xiang H, Zhang W. Review of various NAMPT inhibitors for the treatment of cancer. Front Pharmacol 2022;13:970553.
108. Chini EN. CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions. Curr Pharm Des 2009;15:57-63.
109. Malavasi F, Deaglio S, Funaro A, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev 2008;88:841-86.
110. Philip M, Fairchild L, Sun L, et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 2017;545:452-6.
111. Manna A, Kellett T, Aulakh S, et al. Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses. Blood Adv 2020;4:2143-57.
112. Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F. CD38: a target for immunotherapeutic approaches in multiple myeloma. Front Immunol 2018;9:2722.
113. Malavasi F, Deaglio S, Damle R, Cutrona G, Ferrarini M, Chiorazzi N. CD38 and chronic lymphocytic leukemia: a decade later. Blood 2011;118:3470-8.
114. Chen L, Diao L, Yang Y, et al. CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade. Cancer Discov 2018;8:1156-75.
115. Konen JM, Fradette JJ, Gibbons DL. The good, the bad and the unknown of CD38 in the metabolic microenvironment and immune cell functionality of solid tumors. Cells 2019;9:52.
116. Vaisitti T, Audrito V, Serra S, et al. NAD+-metabolizing ecto-enzymes shape tumor-host interactions: the chronic lymphocytic leukemia model. FEBS Lett 2011;585:1514-20.
117. Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med 2015;373:1207-19.
118. Moreau P, Dimopoulos MA, Yong K, et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncol 2020;16:4347-58.
119. Raab MS, Engelhardt M, Blank A, et al. MOR202, a novel anti-CD38 monoclonal antibody, in patients with relapsed or refractory multiple myeloma: a first-in-human, multicentre, phase 1-2a trial. Lancet Haematol 2020;7:e381-94.
120. Ugamraj HS, Dang K, Ouisse LH, et al. TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs 2022;14:2095949.
121. Tarragó MG, Chini CCS, Kanamori KS, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD+ decline. Cell Metab 2018;27:1081-95.e10.
122. Lagu B, Wu X, Kulkarni S, et al. Orally bioavailable enzymatic inhibitor of CD38, MK-0159, protects against ischemia/reperfusion injury in the murine heart. J Med Chem 2022;65:9418-46.
123. Peyraud F, Guegan JP, Bodet D, Cousin S, Bessede A, Italiano A. Targeting tryptophan catabolism in cancer immunotherapy era: challenges and perspectives. Front Immunol 2022;13:807271.
124. Chen CL, Hsu SC, Ann DK, Yen Y, Kung HJ. Arginine signaling and cancer metabolism. Cancers 2021;13:3541.
125. Christiansen B, Wellendorph P, Bräuner-Osborne H. Known regulators of nitric oxide synthase and arginase are agonists at the human G-protein-coupled receptor GPRC6A. Br J Pharmacol 2006;147:855-63.
127. Cervelli M, Pietropaoli S, Signore F, Amendola R, Mariottini P. Polyamines metabolism and breast cancer: state of the art and perspectives. Breast Cancer Res Treat 2014;148:233-48.
128. Gerner EW, Bruckheimer E, Cohen A. Cancer pharmacoprevention: targeting polyamine metabolism to manage risk factors for colon cancer. J Biol Chem 2018;293:18770-8.
129. Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V. Nitric oxide and cancer: a review. World J Surg Oncol 2013;11:118.
130. Changou CA, Chen YR, Xing L, et al. Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy. Proc Natl Acad Sci U S A 2014;111:14147-52.
131. Cheng CT, Qi Y, Wang YC, et al. Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction. Commun Biol 2018;1:178.
132. Qiu F, Chen YR, Liu X, et al. Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells. Sci Signal 2014;7:ra31.
133. Delage B, Luong P, Maharaj L, et al. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 2012;3:e342.
134. Kim RH, Coates JM, Bowles TL, et al. Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis. Cancer Res 2009;69:700-8.
135. Kremer JC, Prudner BC, Lange SES, et al. Arginine deprivation inhibits the warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-Deficient cancers. Cell Rep 2017;18:991-1004.
136. Wang W, Zou W. Amino acids and their transporters in T Cell immunity and cancer therapy. Mol Cell 2020;80:384-95.
137. Crump NT, Hadjinicolaou AV, Xia M, et al. Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation. Cell Rep 2021;35:109101.
138. Gannon PO, Godin-Ethier J, Hassler M, et al. Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer. PLoS One 2010;5:e12107.
139. Tate DJ Jr, Vonderhaar DJ, Caldas YA, et al. Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma. J Hematol Oncol 2008;1:14.
140. Porembska Z, Luboiński G, Chrzanowska A, Mielczarek M, Magnuska J, Barańczyk-Kuźma A. Arginase in patients with breast cancer. Clin Chim Acta 2003;328:105-11.
141. Chen C, Jiang X, Zhao Z. Inhibition or promotion, the potential role of arginine metabolism in immunotherapy for colorectal cancer. All Life 2023;16:2163306.
142. Rodriguez PC, Quiceno DG, Zabaleta J, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res 2004;64:5839-49.
143. Norian LA, Rodriguez PC, O’Mara LA, et al. Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism. Cancer Res 2009;69:3086-94.
144. Ino Y, Yamazaki-Itoh R, Oguro S, et al. Arginase II expressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer. PLoS One 2013;8:e55146.
145. Sippel TR, White J, Nag K, et al. Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I. Clin Cancer Res 2011;17:6992-7002.
146. Ren W, Zhang X, Li W, et al. Circulating and tumor-infiltrating arginase 1-expressing cells in gastric adenocarcinoma patients were mainly immature and monocytic Myeloid-derived suppressor cells. Sci Rep 2020;10:8056.
147. Lowe MM, Boothby I, Clancy S, et al. Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues. JCI Insight 2019;4:129756.
148. Gunji Y, Hori S, Aoe T, et al. High frequency of cancer patients with abnormal assembly of the T cell receptor-CD3 complex in peripheral blood T lymphocytes. Jpn J Cancer Res 1994;85:1189-92.
149. Zea AH, Rodriguez PC, Culotta KS, et al. L-Arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes. Cell Immunol 2004;232:21-31.
150. Sosnowska A, Chlebowska-Tuz J, Matryba P, et al. Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma. Oncoimmunology 2021;10:1956143.
151. Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood 2007;109:1568-73.
152. Geiger R, Rieckmann JC, Wolf T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 2016;167:829-42.e13.
153. Czystowska-Kuzmicz M, Sosnowska A, Nowis D, et al. Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma. Nat Commun 2019;10:3000.
154. Munder M, Engelhardt M, Knies D, et al. Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion. PLoS One 2013;8:e63521.
155. Mussai F, Wheat R, Sarrou E, et al. Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. Int J Cancer 2019;145:2201-8.
156. Aaboe Jørgensen M, Ugel S, Linder Hübbe M, et al. Arginase 1-based immune modulatory vaccines induce anticancer immunity and synergize with anti-PD-1 checkpoint blockade. Cancer Immunol Res 2021;9:1316-26.
157. Satoh Y, Kotani H, Iida Y, Taniura T, Notsu Y, Harada M. Supplementation of l-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy. Cancer Sci 2020;111:2248-58.
158. 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;18:94-100.
159. Canale FP, Basso C, Antonini G, et al. Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature 2021;598:662-6.
160. Grzybowski MM, Stańczak PS, Pomper P, et al. OATD-02 validates the benefits of pharmacological inhibition of arginase 1 and 2 in cancer. Cancers 2022;14:3967.
161. Borek B, Nowicka J, Gzik A, et al. Arginase 1/2 inhibitor OATD-02: From discovery to first-in-man setup in cancer immunotherapy. Mol Cancer Ther 2023;22:807-17.
162. Pilanc P, Wojnicki K, Roura AJ, et al. A novel oral arginase 1/2 inhibitor enhances the antitumor effect of PD-1 inhibition in murine experimental gliomas by altering the immunosuppressive environment. Front Oncol 2021;11:703465.
163. Naing A, Bauer T, Papadopoulos K, et al. Phase I study of the arginase inhibitor INCB001158 (1158) alone and in combination with pembrolizumab (PEM) in patients (Pts) with advanced/metastatic (adv/met) solid tumours. Ann Oncol 2019;30:v160.
164. Koyama T, Shimizu T, Matsubara N, et al. MO10-6 Phase 1 study of retifanlimab (anti-PD-1) and INCB001158 (arginase inhibitor), alone or in combination, in solid tumors. Ann Oncol 2021;32:S302.
165. Papadopoulos KP, Tsai FYC, Bauer TM, et al. CX-1158-101: a first-in-human phase 1 study of CB-1158, a small molecule inhibitor of arginase, as monotherapy and in combination with an anti-PD-1 checkpoint inhibitor in patients (pts) with solid tumors. J Clin Oncol 2017;35:3005.
166. Altman BJ, Stine ZE, Dang CV. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 2016;16:749.
167. Wise DR, Thompson CB. Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 2010;35:427-33.
168. Son J, Lyssiotis CA, Ying H, et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 2013;496:101-5.
169. Fan J, Kamphorst JJ, Mathew R, et al. Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia. Mol Syst Biol 2013;9:712.
170. Durán RV, Oppliger W, Robitaille AM, et al. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell 2012;47:349-58.
171. Metallo CM, Gameiro PA, Bell EL, et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 2011;481:380-4.
172. Yoo HC, Park SJ, Nam M, et al. A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells. Cell Metab 2020;31:267-83.e12.
173. Ishak Gabra MB, Yang Y, Li H, et al. Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth. Nat Commun 2020;11:3326.
174. Nakaya M, Xiao Y, Zhou X, et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 2014;40:692-705.
175. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 2013;14:500-8.
176. Carr EL, Kelman A, Wu GS, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 2010;185:1037-44.
177. Presnell SR, Spear HK, Durham J, Riddle T, Applegate A, Lutz CT. Correction: differential fuel requirements of human NK cells and human CD8 T cells: glutamine regulates glucose uptake in strongly activated CD8 T cells. Immunohorizons 2020;4:454.
178. Edwards DN, Ngwa VM, Raybuck AL, et al. Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest 2021;131:140100.
179. 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;14:1124-40.
180. Nabe S, Yamada T, Suzuki J, et al. Reinforce the antitumor activity of CD8+ T cells via glutamine restriction. Cancer Sci 2018;109:3737-50.
181. Fu Q, Xu L, Wang Y, et al. Tumor-associated macrophage-derived interleukin-23 interlinks kidney cancer glutamine addiction with immune evasion. Eur Urol 2019;75:752-63.
182. Ma G, Liang Y, Chen Y, et al. Glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer. Mol Cancer Res 2020;18:324-39.
183. Byun JK, Park M, Lee S, et al. Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity. Mol Cell 2020;80:592-606.e8.
184. Leone RD, Zhao L, Englert JM, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019;366:1013-21.
185. Pons-Tostivint E, Lugat A, Fontenau JF, Denis MG, Bennouna J. STK11/LKB1 modulation of the immune response in lung cancer: from biology to therapeutic impact. Cells 2021;10:3129.
186. Aggarwal C, Thompson JC, Chien AL, et al. Baseline plasma tumor mutation burden predicts response to pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer. Clin Cancer Res 2020;26:2354-61.
187. Biton J, Mansuet-Lupo A, Pécuchet N, et al. TP53, STK11, and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinoma. Clin Cancer Res 2018;24:5710-23.
188. Skoulidis F, Goldberg ME, Greenawalt DM, et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov 2018;8:822-35.
189. Best SA, Gubser PM, Sethumadhavan S, et al. Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer. Cell Metab 2022;34:874-87.e6.
190. Sanderson SM, Gao X, Dai Z, Locasale JW. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat Rev Cancer 2019;19:625-37.
191. Neidhart M. DNA methylation and complex human disease. Academic Press; 2015. p. 429-39. Available from: https://www.sciencedirect.com/book/9780124201941/dna-methylation-and-complex-human-disease. [Last accessed on 30 Aug 2023].
192. Ouyang Y, Wu Q, Li J, Sun S, Sun S. S-adenosylmethionine: a metabolite critical to the regulation of autophagy. Cell Prolif 2020;53:e12891.
193. Froese DS, Fowler B, Baumgartner MR. Vitamin B12, folate, and the methionine remethylation cycle - biochemistry, pathways, and regulation. J Inherit Metab Dis 2019;42:673-85.
194. Lückerath K, Lapa C, Albert C, et al. 11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma. Oncotarget 2015;6:8418-29.
195. Glaudemans AWJM, Enting RH, Heesters MAAM, et al. Value of 11C-methionine PET in imaging brain tumours and metastases. Eur J Nucl Med Mol Imaging 2013;40:615-35.
196. Wang Z, Yip LY, Lee JHJ, et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat Med 2019;25:825-37.
197. Zhao L, Su H, Liu X, et al. mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A. Cell Biosci 2022;12:183.
198. Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol 2013;9:300-6.
199. Sinclair LV, Howden AJ, Brenes A, et al. Antigen receptor control of methionine metabolism in T cells. eLife 2019;8:e44210.
200. Hung MH, Lee JS, Ma C, et al. Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma. Nat Commun 2021;12:1455.
201. Albers E. Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5'-methylthioadenosine. IUBMB Life 2009;61:1132-42.
202. Li T, Tan YT, Chen YX, et al. Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts. Gut 2023;72:501-11.
203. Bian Y, Li W, Kremer DM, et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature 2020;585:277-82.
204. Tripathi P, Kurtulus S, Wojciechowski S, et al. STAT5 is critical to maintain effector CD8+ T cell responses. J Immunol 2010;185:2116-24.
205. Xu S, Chaudhary O, Rodríguez-Morales P, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 2021;54:1561-77.e7.
206. Zhang Y, Kurupati R, Liu L, et al. Enhancing CD8+ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 2017;32:377-91.e9.
207. Ma X, Bi E, Lu Y, et al. Cholesterol Induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab 2019;30:143-56.e5.
208. Mollinedo F, Gajate C. Lipid rafts as signaling hubs in cancer cell survival/death and invasion: implications in tumor progression and therapy: thematic review series: biology of lipid rafts. J Lipid Res 2020;61:611-35.
209. Ridker PM. LDL cholesterol: controversies and future therapeutic directions. Lancet 2014;384:607-17.
210. Gelissen IC, Harris M, Rye KA, et al. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol 2006;26:534-40.
211. Cruz ALS, Barreto EA, Fazolini NPB, Viola JPB, Bozza PT. Lipid droplets: platforms with multiple functions in cancer hallmarks. Cell Death Dis 2020;11:105.
212. Yue S, Li J, Lee SY, et al. Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness. Cell Metab 2014;19:393-406.
213. Antalis CJ, Arnold T, Rasool T, Lee B, Buhman KK, Siddiqui RA. High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast Cancer Res Treat 2010;122:661-70.
214. Mayengbam SS, Singh A, Pillai AD, Bhat MK. Influence of cholesterol on cancer progression and therapy. Transl Oncol 2021;14:101043.
215. Dong F, Mo Z, Eid W, Courtney KC, Zha X. Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1. PLoS One 2014;9:e113789.
216. Porstmann T, Santos CR, Griffiths B, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008;8:224-36.
217. Li J, Gu D, Lee SS, et al. Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer. Oncogene 2016;35:6378-88.
218. Thysell E, Surowiec I, Hörnberg E, et al. Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol. PLoS One 2010;5:e14175.
219. Lei K, Kurum A, Kaynak M, et al. Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy. Nat Biomed Eng 2021;5:1411-25.
220. Huang B, Song BL, Xu C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat Metab 2020;2:132-41.
221. Maxwell KN, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci U S A 2005;102:2069-74.
222. Zhang DW, Lagace TA, Garuti R, et al. Binding of proprotein convertase subtilisin/kexin type 9 to epidermal growth factor-like repeat A of low density lipoprotein receptor decreases receptor recycling and increases degradation. J Biol Chem 2007;282:18602-12.
223. Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest 2006;116:2995-3005.
224. Poirier S, Mayer G, Poupon V, et al. Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route. J Biol Chem 2009;284:28856-64.
225. Gu Y, Lin X, Dong Y, et al. PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity. J Exp Clin Cancer Res 2023;42:2.
226. Yuan J, Cai T, Zheng X, et al. Potentiating CD8+ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling. Protein Cell 2021;12:240-60.
227. Liu X, Bao X, Hu M, et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer. Nature 2020;588:693-8.
228. Ni W, Mo H, Liu Y, et al. Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation. Mol Ther 2021;29:2995-3010.
229. Lim WJ, Lee M, Oh Y, et al. Statins decrease programmed death-ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling. Cells 2021;10:2488.
230. Choe EJ, Lee CH, Bae JH, Park JM, Park SS, Baek MC. Atorvastatin enhances the efficacy of immune checkpoint therapy and suppresses the cellular and extracellular vesicle PD-L1. Pharmaceutics 2022;14:1660.
231. Wang Q, Cao Y, Shen L, et al. Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs. Sci Adv 2022;8:eabq4722.
232. Tatsuguchi T, Uruno T, Sugiura Y, et al. Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells. Int Immunol 2022;34:277-89.
233. Zech T, Ejsing CS, Gaus K, et al. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J 2009;28:466-76.
234. Liu X, Zhao Z, Sun X, et al. Blocking cholesterol metabolism with tumor-penetrable nanovesicles to improve photodynamic cancer immunotherapy. Small Methods 2023;7:2200898.
235. Lee IK, Song H, Kim H, et al. RORα regulates cholesterol metabolism of CD8+ T cells for anticancer immunity. Cancers 2020;12:1733.
236. Yang W, Bai Y, Xiong Y, et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 2016;531:651-5.
237. You W, Ke J, Chen Y, et al. SQLE, a key enzyme in cholesterol metabolism, correlates with tumor immune infiltration and immunotherapy outcome of pancreatic adenocarcinoma. Front Immunol 2022;13:864244.
238. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008;7:489-503.
239. Guillou H, Zadravec D, Martin PG, Jacobsson A. The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice. Prog Lipid Res 2010;49:186-99.
240. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 2013;13:227-32.
241. Lou W, Gong C, Ye Z, et al. Lipid metabolic features of T cells in the tumor microenvironment. Lipids Health Dis 2022;21:94.
242. Tomin T, Fritz K, Gindlhuber J, et al. Deletion of adipose triglyceride lipase links triacylglycerol accumulation to a more-aggressive phenotype in A549 lung carcinoma cells. J Proteome Res 2018;17:1415-25.
243. Snaebjornsson MT, Janaki-Raman S, Schulze A. Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer. Cell Metab 2020;31:62-76.
244. Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: understanding the molecular basis. Nat Rev Cancer 2014;14:754-62.
245. Nieman KM, Kenny HA, Penicka CV, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011;17:1498-503.
246. Wang YY, Attané C, Milhas D, et al. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2017;2:e87489.
247. Ye H, Adane B, Khan N, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell 2016;19:23-37.
248. Wen YA, Xing X, Harris JW, et al. Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer. Cell Death Dis 2017;8:e2593.
249. Ringel AE, Drijvers JM, Baker GJ, et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity. Cell 2020;183:1848-66.e26.
250. Zhang C, Yue C, Herrmann A, et al. STAT3 activation-induced fatty acid oxidation in CD8+ T effector cells is critical for obesity-promoted breast tumor growth. Cell Metab 2020;31:148-61.e5.
251. Patsoukis N, Bardhan K, Chatterjee P, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 2015;6:6692.
252. Wang Z, Aguilar EG, Luna JI, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 2019;25:141-51.
253. Manzo T, Prentice BM, Anderson KG, et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells. J Exp Med 2020;217:e20191920.
254. Huang SC, Everts B, Ivanova Y, et al. Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages. Nat Immunol 2014;15:846-55.
255. Wang H, Franco F, Tsui YC, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 2020;21:298-308.
256. Yan D, Adeshakin AO, Xu M, et al. Lipid metabolic pathways confer the immunosuppressive function of myeloid-derived suppressor cells in tumor. Front Immunol 2019;10:1399.
257. Hossain F, Al-Khami AA, Wyczechowska D, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies. Cancer Immunol Res 2015;3:1236-47.
258. Auciello FR, Bulusu V, Oon C, et al. A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression. Cancer Discov 2019;9:617-27.
259. Federico L, Jeong KJ, Vellano CP, Mills GB. Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression. J Lipid Res 2016;57:25-35.
260. Matas-Rico E, Frijlink E, van der Haar Àvila I, et al. Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8+ T cells. Cell Rep 2021;37:110013.
261. Mathew D, Kremer KN, Strauch P, Tigyi G, Pelanda R, Torres RM. LPA5 is an inhibitory receptor that suppresses CD8 T-cell cytotoxic function via disruption of early TCR signaling. Front Immunol 2019;10:1159.
262. Oda SK, Strauch P, Fujiwara Y, et al. Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression. Cancer Immunol Res 2013;1:245-55.
263. Kremer KN, Buser A, Thumkeo D, et al. LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation. Proc Natl Acad Sci U S A 2022;119:e2118816119.
264. Turner JA, Fredrickson MA, D’Antonio M, et al. Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity. Nat Commun 2023;14:3214.
265. Deken M, Niewola K, Matas-rico E, et al. 922 A novel autotaxin inhibitor, IOA-289, modulates tumor, immune and stromal cell function and has monotherapy activity in fibrotic cancer models. J Immunother Cancer 2021;9:A967.
266. Deken MA, Niewola-Staszkowska K, Peyruchaud O, et al. Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors. Immunooncol Technol 2023;18:100384.
267. Xiong Q, Feng D, Wang Z, et al. Fatty acid synthase is the key regulator of fatty acid metabolism and is related to immunotherapy in bladder cancer. Front Immunol 2022;13:836939.
268. Wang Q, Tian N, Zhang W, et al. Fatty acid synthase mutations predict favorable immune checkpoint inhibitor outcome and response in melanoma and non-small cell lung cancer patients. Cancers 2022;14:5638.
269. Murphy WJ, Longo DL. The surprisingly positive association between obesity and cancer immunotherapy efficacy. JAMA 2019;321:1247-8.
270. Woodall MJ, Neumann S, Campbell K, Pattison ST, Young SL. The effects of obesity on anti-cancer immunity and cancer immunotherapy. Cancers 2020;12:1230.
271. McQuade JL, Daniel CR, Hess KR, et al. Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet Oncol 2018;19:310-22.
272. Cortellini A, Bersanelli M, Buti S, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer 2019;7:57.
273. Diana A, Wang LM, D'Costa Z, et al. Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma. Oncotarget 2016;7:40992-1004.
274. Shen T, Zhou L, Shen H, et al. Prognostic value of programmed cell death protein 1 expression on CD8+ T lymphocytes in pancreatic cancer. Sci Rep 2017;7:7848.