Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment

Abstract

The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.

Keywords

Immunotherapy resistance / tumor-immune microenvironment / immune checkpoint blockade / energy metabolism / amino acid metabolism / lipid metabolism

References

[1] Pardoll DM.The blockade of immune checkpoints in cancer immunotherapy.Nat Rev Cancer2012;12:252-64 PMCID:PMC4856023

[2] Thommen DS.T cell dysfunction in cancer.Cancer Cell2018;33:547-62 PMCID:PMC7116508

[3] Chen L.Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future.J Clin Invest2015;125:3384-91 PMCID:PMC4588282

[4] Morad G,Sharma P.Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.Cell2021;184:5309-37 PMCID:PMC8767569

[5] Warburg O,Negelein E.The metabolism of tumors in the body.J Gen Physiol1927;8:519-30 PMCID:PMC2140820

[6] Hanahan D.Hallmarks of cancer: new dimensions.Cancer Discov2022;12:31-46

[7] Pavlova NN,Thompson CB.The hallmarks of cancer metabolism: still emerging.Cell Metab2022;34:355-77 PMCID:PMC8891094

[8] Leone RD.Metabolism of immune cells in cancer.Nat Rev Cancer2020;20:516-31 PMCID:PMC8041116

[9] Binnewies M,Kersten K.Understanding the tumor immune microenvironment (TIME) for effective therapy.Nat Med2018;24:541-50 PMCID:PMC5998822

[10] Roy DG,Williams KS,Jones RG.Immunometabolism in the tumor microenvironment.Annu Rev Cancer Biol2021;5:137-59

[11] Brown TP.Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon.Pharmacol Ther2020;206:107451

[12] Halestrap AP.The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation.Biochem J1999;343:281-99 PMCID:PMC1220552

[13] Halestrap AP.The SLC16 gene family - structure, role and regulation in health and disease.Mol Aspects Med2013;34:337-49

[14] Sandforth L,Dinges LA.Impact of the monocarboxylate transporter-1 (MCT1)-mediated cellular import of lactate on stemness properties of human pancreatic adenocarcinoma cells †.Cancers2020;12:581 PMCID:PMC7139999

[15] Longhitano L,Orlando L.The crosstalk between GPR81/IGFBP6 promotes breast cancer progression by modulating lactate metabolism and oxidative stress.Antioxidants2022;11:275 PMCID:PMC8868469

[16] Boedtkjer E.The acidic tumor microenvironment as a driver of cancer.Annu Rev Physiol2020;82:103-26

[17] Notarangelo G,Perez EM.Oncometabolite _D-2HG alters T cell metabolism to impair CD8⁺ T cell function.Science2022;377:1519-29 PMCID:PMC9629749

[18] Hermans D,García-Cañaveras JC.Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8⁺ T cell stemness and antitumor immunity.Proc Natl Acad Sci U S A2020;117:6047-55 PMCID:PMC7084161

[19] Rostamian H,Jafarzadeh L.Restricting tumor lactic acid metabolism using dichloroacetate improves T cell functions.BMC Cancer2022;22:39 PMCID:PMC8734242

[20] Franchina DG,Brenner D.Reactive oxygen species: involvement in T cell signaling and metabolism.Trends Immunol2018;39:489-502

[21] Fischer K,Voelkl S.Inhibitory effect of tumor cell-derived lactic acid on human T cells.Blood2007;109:3812-9

[22] Brand A,Koehl GE.LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells.Cell Metab2016;24:657-71

[23] Macian F.NFAT proteins: key regulators of T-cell development and function.Nat Rev Immunol2005;5:472-84

[24] Ping W,Li G,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 Biochem2018;49:828-36

[25] Pauken KE.Overcoming T cell exhaustion in infection and cancer.Trends Immunol2015;36:265-76 PMCID:PMC4393798

[26] Kaymak I,Duimstra LR.Carbon source availability drives nutrient utilization in CD8⁺ T cells.Cell Metab2022;34:1298-311.e6 PMCID:PMC10068808

[27] Hui S,Morscher RJ.Glucose feeds the TCA cycle via circulating lactate.Nature2017;551:115-8 PMCID:PMC5898814

[28] Faubert B,Cai L.Lactate metabolism in human lung tumors.Cell2017;171:358-71.e9 PMCID:PMC5684706

[29] Quinn WJ 3rd,TeSlaa T.Lactate limits T cell proliferation via the NAD(H) redox state.Cell Rep2020;33:108500 PMCID:PMC7830708

[30] Xia H,Crespo J.Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity.Sci Immunol2017;2:eaan4631 PMCID:PMC5774333

[31] Elia I,Johnson S.Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8⁺ T cells.Cell Metab2022;34:1137-50.e6 PMCID:PMC9357162

[32] Angelin A,Dahiya S.Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments.Cell Metab2017;25:1282-93.e7 PMCID:PMC5462872

[33] Watson MJ,Mullett SJ.Metabolic support of tumour-infiltrating regulatory T cells by lactic acid.Nature2021;591:645-51 PMCID:PMC7990682

[34] Stone SC,Alvarez KLF.Lactate secreted by cervical cancer cells modulates macrophage phenotype.J Leukoc Biol2019;105:1041-54

[35] Kelderman S,van Tinteren H.Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma.Cancer Immunol Immunother2014;63:449-58

[36] Nosrati A,Goldinger SM.Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy.Br J Cancer2017;116:1141-7 PMCID:PMC5418446

[37] Zhang Z,Yan X.Pretreatment lactate dehydrogenase may predict outcome of advanced non small-cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis.Cancer Med2019;8:1467-73 PMCID:PMC6488146

[38] Schouwenburg MG,Koornstra RHT.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?.Cancer2019;11:1940 PMCID:PMC6966631

[39] Wang X,Chen X.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 Cancer2019;10:1395-401 PMCID:PMC6558460

[40] Yin TT,Wang F.Lactate score predicts survival, immune cell infiltration and response to immunotherapy in breast cancer.Front Genet2022;13:943849 PMCID:PMC9421043

[41] Renner K,Schnell A.Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy.Cell Rep2019;29:135-50.e9

[42] Li N,Wang L.ALKBH5 regulates anti-PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment.Proc Natl Acad Sci U S A2020;117:20159-70 PMCID:PMC7443867

[43] Kumagai S,Itahashi K.Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments.Cancer Cell2022;40:201-18.e9

[44] Stransky N.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.Biomolecules2022;12:573 PMCID:PMC9031823

[45] Feng Q,Yu X.Lactate increases stemness of CD8  + T cells to augment anti-tumor immunity.Nat Commun2022;13:4981 PMCID:PMC9448806

[46] Kaczmarek E,Sévigny J.Identification and characterization of CD39/vascular ATP diphosphohydrolase.J Biol Chem1996;271:33116-22

[47] Zimmermann H.5'-nucleotidase: molecular structure and functional aspects.Biochem J1992;285:345-65 PMCID:PMC1132794

[48] Horenstein AL,Zaccarello G.A CD38/CD203a/CD73 ectoenzymatic pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes.Oncoimmunology2013;2:e26246 PMCID:PMC3850273

[49] Campos-Contreras ADR,Vázquez-Cuevas FG.Purinergic signaling in the hallmarks of cancer.Cells2020;9:1612 PMCID:PMC7407645

[50] Allard B,Robson SC.The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets.Immunol Rev2017;276:121-44 PMCID:PMC5338647

[51] Ferretti E,Canzonetta C,Morandi F.Canonical and non-canonical adenosinergic pathways.Immunol Lett2019;205:25-30

[52] Allard B,Buisseret L.Publisher correction: the adenosine pathway in immuno-oncology.Nat Rev Clin Oncol2020;17:650

[53] Virgilio F, Adinolfi E. Extracellular purines, purinergic receptors and tumor growth.Oncogene2017;36:293-303 PMCID:PMC5269532

[54] Pellegatti P,Bianchi G,Pistoia V.Increased level of extracellular ATP at tumor sites: in vivo imaging with plasma membrane luciferase.PLoS One2008;3:e2599 PMCID:PMC2440522

[55] Mora-García ML,García-Rocha R.Cervical cancer cells suppress effector functions of cytotoxic T cells through the adenosinergic pathway.Cell Immunol2017;320:46-55

[56] Sundström P,Langenes V.Regulatory T cells from colon cancer patients inhibit effector T-cell migration through an adenosine-dependent mechanism.Cancer Immunol Res2016;4:183-93

[57] Shi L,Du S.Adenosine generated by regulatory T Cells induces CD8⁺ T cell exhaustion in gastric cancer through A2aR pathway.Biomed Res Int2019;2019:4093214 PMCID:PMC6942766

[58] Maj T,Crespo J.Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor.Nat Immunol2017;18:1332-41 PMCID:PMC5770150

[59] Giatromanolaki A,Pouliliou S.Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways.Life Sci2020;259:118389

[60] Vignali PDA,Watson MJ.Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity.Nat Immunol2023;24:267-79 PMCID:PMC10402660

[61] Ohta A,Ohta A,Madasu M.The development and immunosuppressive functions of CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells are under influence of the adenosine-A2A adenosine receptor pathway.Front Immunol2012;3:190 PMCID:PMC3389649

[62] Torres-Pineda DB,García-Rocha R.Adenosine augments the production of IL-10 in cervical cancer cells through interaction with the A_2B adenosine receptor, resulting in protection against the activity of cytotoxic T cells.Cytokine2020;130:155082

[63] King RJ,He C.CD73 induces GM-CSF/MDSC-mediated suppression of T cells to accelerate pancreatic cancer pathogenesis.Oncogene2022;41:971-82 PMCID:PMC8840971

[64] Ludwig N,Azambuja JH.Tumor-derived exosomes promote angiogenesis via adenosine A_2B receptor signaling.Angiogenesis2020;23:599-610 PMCID:PMC7529853

[65] Ploeg EM,Britsch I.Bispecific antibody CD73xEpCAM selectively inhibits the adenosine-mediated immunosuppressive activity of carcinoma-derived extracellular vesicles.Cancer Lett2021;521:109-18

[66] Morandi F,Horenstein AL,Malavasi F.Microvesicles expressing adenosinergic ectoenzymes and their potential role in modulating bone marrow infiltration by neuroblastoma cells.Oncoimmunology2019;8:e1574198 PMCID:PMC6492972

[67] Clayton A,Webber J,Tabi Z.Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production.J Immunol2011;187:676-83

[68] Chimote AA,Arnold MJ.A defect in KCa3.1 channel activity limits the ability of CD8⁺ T cells from cancer patients to infiltrate an adenosine-rich microenvironment.Sci Signal2018;11:eaaq1616 PMCID:PMC6006512

[69] Chimote AA,Kucher V.Selective inhibition of KCa3.1 channels mediates adenosine regulation of the motility of human T cells.J Immunol2013;191:6273-80 PMCID:PMC4415878

[70] Feske S,Prakriya M.Ion channels and transporters in lymphocyte function and immunity.Nat Rev Immunol2012;12:532-47 PMCID:PMC3670817

[71] Newton HS,Chimote AA.PD1 blockade enhances K⁺ channel activity, Ca²⁺ signaling, and migratory ability in cytotoxic T lymphocytes of patients with head and neck cancer.J Immunother Cancer2020;8:e000844 PMCID:PMC7566435

[72] Deaglio S,Gao W.Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression.J Exp Med2007;204:1257-65 PMCID:PMC2118603

[73] Mandapathil M,Szajnik M.Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer.Clin Cancer Res2009;15:6348-57 PMCID:PMC2763335

[74] Koyas A,Kayhan M,Akdemir I.Interleukin-7 protects CD8⁺ T cells from adenosine-mediated immunosuppression.Sci Signal2021;14:eabb1269

[75] Cekic C.Adenosine A_2A receptors intrinsically regulate CD8⁺ T cells in the tumor microenvironment.Cancer Res2014;74:7239-49 PMCID:PMC4459794

[76] Huang S,Koshiba M.Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion.Blood1997;90:1600-10

[77] Ohta A,Prasad SJ.A2A adenosine receptor protects tumors from antitumor T cells.Proc Natl Acad Sci U S A2006;103:13132-7 PMCID:PMC1559765

[78] Kjaergaard J,Jones G,Sitkovsky M.A_2A adenosine receptor gene deletion or synthetic A_2A antagonist liberate tumor-reactive CD8⁺ T cells from tumor-induced immunosuppression.J Immunol2018;201:782-91 PMCID:PMC6052792

[79] Newton HS,Arnold MJ,Conforti L.Targeted knockdown of the adenosine A_2A receptor by lipid NPs rescues the chemotaxis of head and neck cancer memory T cells.Mol Ther Methods Clin Dev2021;21:133-43 PMCID:PMC8005736

[80] Ma SR,Liu JF.Blockade of adenosine A2A receptor enhances CD8⁺ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma.Mol Cancer2017;16:99 PMCID:PMC5461710

[81] Ohta A,Madasu M.A2A adenosine receptor may allow expansion of T cells lacking effector functions in extracellular adenosine-rich microenvironments¹.J Immunol2009;183:5487-93

[82] Moesta AK,Smyth MJ.Targeting CD39 in cancer.Nat Rev Immunol2020;20:739-55

[83] Sidders B,Goodwin K.Adenosine signaling is prognostic for cancer outcome and has predictive utility for immunotherapeutic response.Clin Cancer Res2020;26:2176-87

[84] Fong L,Powderly JD.Adenosine 2A receptor blockade as an immunotherapy for treatment-refractory renal cell cancer.Cancer Discov2020;10:40-53 PMCID:PMC6954326

[85] Bai Y,Zheng J,Yang Z.Overcoming high level adenosine-mediated immunosuppression by DZD2269, a potent and selective A2aR antagonist.J Exp Clin Cancer Res2022;41:302 PMCID:PMC9563815

[86] Buisseret L,De Bono JS.Phase 1 trial of the adenosine A_2A receptor antagonist inupadenant (EOS-850): update on tolerability, and antitumor activity potentially associated with the expression of the A_2A receptor within the tumor.J Clin Oncol2021;39:2562

[87] Lu JC,Huang XY.Amplification of spatially isolated adenosine pathway by tumor-macrophage interaction induces anti-PD1 resistance in hepatocellular carcinoma.J Hematol Oncol2021;14:200 PMCID:PMC8627086

[88] Powderly J,Carneiro B.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 Oncol2020;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,Eyles J.190P Combination of IPH5201, a blocking antibody targeting the CD39 immunosuppressive pathway, with durvalumab and chemotherapies: preclinical rationale.Immuno-Oncol Technol2022;16:100302

[91] Wainberg Z,Lee KW.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 Res2022;82:CT015

[92] Bendell J,Overman M.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 Immunother2023;72:2443-58 PMCID:PMC10264501

[93] Herbst RS,Barlesi F.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 Oncol2022;40:3383-93

[94] Yu W,Wang X.Boosting cancer immunotherapy via the convenient A2AR inhibition using a tunable nanocatalyst with light-enhanced activity.Adv Mater2022;34:2106967

[95] Wu L,Li Y.Biomimetic nanocarriers guide extracellular ATP homeostasis to remodel energy metabolism for activating innate and adaptive immunity system.Adv Sci2022;9:2105376 PMCID:PMC9189650

[96] Mao C,Fu J.Delivery of an ectonucleotidase inhibitor with ROS-responsive nanoparticles overcomes adenosine-mediated cancer immunosuppression.Sci Transl Med2022;14:eabh1261 PMCID:PMC9499735

[97] Covarrubias AJ,Grozio A.NAD⁺ metabolism and its roles in cellular processes during ageing.Nat Rev Mol Cell Biol2021;22:119-41 PMCID:PMC7963035

[98] Xie N,Gao W.NAD⁺ metabolism: pathophysiologic mechanisms and therapeutic potential.Signal Transduct Target Ther2020;5:227 PMCID:PMC7539288

[99] Dwivedi S,Ortiz-Navarrete V.CD38 and regulation of the immune response cells in cancer.J Oncol2021;2021:6630295 PMCID:PMC7936891

[100] Navas LE.NAD⁺ metabolism, stemness, the immune response, and cancer.Signal Transduct Target Ther2021;6:2 PMCID:PMC7775471

[101] Yaku K,Hikosaka K.NAD metabolism in cancer therapeutics.Front Oncol2018;8:622 PMCID:PMC6315198

[102] Liu HY,Liang JM.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 Oncol2023;149:2743-56 PMCID:PMC10314862

[103] Wang Y,Wang L.NAD⁺ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells.Cell Rep2021;36:109516

[104] Gerner RR,Reider S.Targeting NAD immunometabolism limits severe graft-versus-host disease and has potent antileukemic activity.Leukemia2020;34:1885-97

[105] Aswad F,Dennert G.High sensitivity of CD4⁺CD25⁺ regulatory T cells to extracellular metabolites nicotinamide adenine dinucleotide and ATP: a role for P2X7 receptors.J Immunol2005;175:3075-83

[106] Hubert S,Klages K.Extracellular NAD⁺ shapes the Foxp3⁺ regulatory T cell compartment through the ART2-P2X7 pathway.J Exp Med2010;207:2561-8 PMCID:PMC2989765

[107] Wei Y,Zhang W.Review of various NAMPT inhibitors for the treatment of cancer.Front Pharmacol2022;13:970553 PMCID:PMC9490061

[108] Chini EN.CD38 as a regulator of cellular NAD: a novel potential pharmacological target for metabolic conditions.Curr Pharm Des2009;15:57-63 PMCID:PMC2883294

[109] Malavasi F,Funaro A.Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology.Physiol Rev2008;88:841-86

[110] Philip M,Sun L.Chromatin states define tumour-specific T cell dysfunction and reprogramming.Nature2017;545:452-6 PMCID:PMC5693219

[111] Manna A,Aulakh S.Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8⁺ T-cell responses.Blood Adv2020;4:2143-57 PMCID:PMC7252547

[112] Morandi F,Costa F,Pistoia V.CD38: a target for immunotherapeutic approaches in multiple myeloma.Front Immunol2018;9:2722 PMCID:PMC6279879

[113] Malavasi F,Damle R,Ferrarini M.CD38 and chronic lymphocytic leukemia: a decade later.Blood2011;118:3470-8 PMCID:PMC3574275

[114] Chen L,Yang Y.CD38-mediated immunosuppression as a mechanism of tumor cell escape from PD-1/PD-L1 blockade.Cancer Discov2018;8:1156-75 PMCID:PMC6205194

[115] Konen JM,Gibbons DL.The good, the bad and the unknown of CD38 in the metabolic microenvironment and immune cell functionality of solid tumors.Cells2019;9:52 PMCID:PMC7016859

[116] Vaisitti T,Serra S.NAD⁺-metabolizing ecto-enzymes shape tumor-host interactions: the chronic lymphocytic leukemia model.FEBS Lett2011;585:1514-20

[117] Lokhorst HM,Laubach JP.Targeting CD38 with daratumumab monotherapy in multiple myeloma.N Engl J Med2015;373:1207-19

[118] Moreau P,Yong K.Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design.Future Oncol2020;16:4347-58

[119] Raab MS,Blank A.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 Haematol2020;7:e381-94

[120] Ugamraj HS,Ouisse LH.TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity.MAbs2022;14:2095949 PMCID:PMC9311320

[121] Tarragó MG,Kanamori KS.A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD⁺ decline.Cell Metab2018;27:1081-95.e10 PMCID:PMC5935140

[122] Lagu B,Kulkarni S.Orally bioavailable enzymatic inhibitor of CD38, MK-0159, protects against ischemia/reperfusion injury in the murine heart.J Med Chem2022;65:9418-46

[123] Peyraud F,Bodet D,Bessede A.Targeting tryptophan catabolism in cancer immunotherapy era: challenges and perspectives.Front Immunol2022;13:807271 PMCID:PMC8841724

[124] Chen CL,Ann DK,Kung HJ.Arginine signaling and cancer metabolism.Cancers2021;13:3541 PMCID:PMC8306961

[125] Christiansen B,Bräuner-Osborne H.Known regulators of nitric oxide synthase and arginase are agonists at the human G-protein-coupled receptor GPRC6A.Br J Pharmacol2006;147:855-63 PMCID:PMC1760712

[126] Gilmour SK.Polyamines and nonmelanoma skin cancer.Toxicol Appl Pharmacol2007;224:249-56 PMCID:PMC2098876

[127] Cervelli M,Signore F,Mariottini P.Polyamines metabolism and breast cancer: state of the art and perspectives.Breast Cancer Res Treat2014;148:233-48

[128] Gerner EW,Cohen A.Cancer pharmacoprevention: targeting polyamine metabolism to manage risk factors for colon cancer.J Biol Chem2018;293:18770-8 PMCID:PMC6290143

[129] Choudhari SK,Bagde S,Joshi V.Nitric oxide and cancer: a review.World J Surg Oncol2013;11:118 PMCID:PMC3669621

[130] Changou CA,Xing L.Arginine starvation-associated atypical cellular death involves mitochondrial dysfunction, nuclear DNA leakage, and chromatin autophagy.Proc Natl Acad Sci U S A2014;111:14147-52 PMCID:PMC4191793

[131] Cheng CT,Wang YC.Arginine starvation kills tumor cells through aspartate exhaustion and mitochondrial dysfunction.Commun Biol2018;1:178 PMCID:PMC6203837

[132] Qiu F,Liu X.Arginine starvation impairs mitochondrial respiratory function in ASS1-deficient breast cancer cells.Sci Signal2014;7:ra31 PMCID:PMC4229039

[133] Delage B,Maharaj L.Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis.Cell Death Dis2012;3:e342 PMCID:PMC3406582

[134] Kim RH,Bowles TL.Arginine deiminase as a novel therapy for prostate cancer induces autophagy and caspase-independent apoptosis.Cancer Res2009;69:700-8 PMCID:PMC2629384

[135] Kremer JC,Lange SES.Arginine deprivation inhibits the warburg effect and upregulates glutamine anaplerosis and serine biosynthesis in ASS1-Deficient cancers.Cell Rep2017;18:991-1004 PMCID:PMC5840045

[136] Wang W.Amino acids and their transporters in T Cell immunity and cancer therapy.Mol Cell2020;80:384-95 PMCID:PMC7655528

[137] Crump NT,Xia M.Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation.Cell Rep2021;35:109101 PMCID:PMC8131582

[138] Gannon PO,Hassler M.Androgen-regulated expression of arginase 1, arginase 2 and interleukin-8 in human prostate cancer.PLoS One2010;5:e12107 PMCID:PMC2920336

[139] Tate DJ Jr,Caldas YA.Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma.J Hematol Oncol2008;1:14 PMCID:PMC2562378

[140] Porembska Z,Chrzanowska A,Magnuska J.Arginase in patients with breast cancer.Clin Chim Acta2003;328:105-11

[141] Chen C,Zhao Z.Inhibition or promotion, the potential role of arginine metabolism in immunotherapy for colorectal cancer.All Life2023;16:2163306

[142] Rodriguez PC,Zabaleta J.Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses.Cancer Res2004;64:5839-49

[143] Norian LA,O’Mara LA.Tumor-infiltrating regulatory dendritic cells inhibit CD8⁺ T cell function via _L-arginine metabolism.Cancer Res2009;69:3086-94 PMCID:PMC2848068

[144] Ino Y,Oguro S.Arginase II expressed in cancer-associated fibroblasts indicates tissue hypoxia and predicts poor outcome in patients with pancreatic cancer.PLoS One2013;8:e55146 PMCID:PMC3570471

[145] Sippel TR,Nag K.Neutrophil degranulation and immunosuppression in patients with GBM: restoration of cellular immune function by targeting arginase I.Clin Cancer Res2011;17:6992-7002

[146] Ren W,Li W.Circulating and tumor-infiltrating arginase 1-expressing cells in gastric adenocarcinoma patients were mainly immature and monocytic Myeloid-derived suppressor cells.Sci Rep2020;10:8056 PMCID:PMC7229115

[147] Lowe MM,Clancy S.Regulatory T cells use arginase 2 to enhance their metabolic fitness in tissues.JCI Insight2019;4:129756 PMCID:PMC6975275

[148] Gunji Y,Aoe T.High frequency of cancer patients with abnormal assembly of the T cell receptor-CD3 complex in peripheral blood T lymphocytes.Jpn J Cancer Res1994;85:1189-92 PMCID:PMC5919393

[149] Zea AH,Culotta KS._L-Arginine modulates CD3ζ expression and T cell function in activated human T lymphocytes.Cell Immunol2004;232:21-31

[150] Sosnowska A,Matryba P.Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma.Oncoimmunology2021;10:1956143 PMCID:PMC8312619

[151] Rodriguez PC,Ochoa AC.L-arginine availability regulates T-lymphocyte cell-cycle progression.Blood2007;109:1568-73 PMCID:PMC1794048

[152] Geiger R,Wolf T.L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity.Cell2016;167:829-42.e13 PMCID:PMC5075284

[153] Czystowska-Kuzmicz M,Nowis D.Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.Nat Commun2019;10:3000 PMCID:PMC6611910

[154] Munder M,Knies D.Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion.PLoS One2013;8:e63521 PMCID:PMC3662698

[155] Mussai F,Sarrou E.Targeting the arginine metabolic brake enhances immunotherapy for leukaemia.Int J Cancer2019;145:2201-8 PMCID:PMC6767531

[156] Aaboe Jørgensen M,Linder Hübbe M.Arginase 1-based immune modulatory vaccines induce anticancer immunity and synergize with anti-PD-1 checkpoint blockade.Cancer Immunol Res2021;9:1316-26

[157] Satoh Y,Iida Y,Notsu Y.Supplementation of l-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy.Cancer Sci2020;111:2248-58 PMCID:PMC7484823

[158] He X,Yuan L.Combination therapy with L-arginine and α-PD-L1 antibody boosts immune response against osteosarcoma in immunocompetent mice.Cancer Biol Ther2017;18:94-100 PMCID:PMC5362985

[159] Canale FP,Antonini G.Metabolic modulation of tumours with engineered bacteria for immunotherapy.Nature2021;598:662-6

[160] Grzybowski MM,Pomper P.OATD-02 validates the benefits of pharmacological inhibition of arginase 1 and 2 in cancer.Cancers2022;14:3967 PMCID:PMC9406419

[161] Borek B,Gzik A.Arginase 1/2 inhibitor OATD-02: From discovery to first-in-man setup in cancer immunotherapy.Mol Cancer Ther2023;22:807-17

[162] Pilanc P,Roura AJ.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 Oncol2021;11:703465 PMCID:PMC8422859

[163] Naing A,Papadopoulos K.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 Oncol2019;30:v160

[164] Koyama T,Matsubara N.MO10-6 Phase 1 study of retifanlimab (anti-PD-1) and INCB001158 (arginase inhibitor), alone or in combination, in solid tumors.Ann Oncol2021;32:S302

[165] Papadopoulos KP,Bauer TM.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 Oncol2017;35:3005

[166] Altman BJ,Dang CV.From Krebs to clinic: glutamine metabolism to cancer therapy.Nat Rev Cancer2016;16:749

[167] Wise DR.Glutamine addiction: a new therapeutic target in cancer.Trends Biochem Sci2010;35:427-33 PMCID:PMC2917518

[168] Son J,Ying H.Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway.Nature2013;496:101-5 PMCID:PMC3656466

[169] Fan J,Mathew R.Glutamine-driven oxidative phosphorylation is a major ATP source in transformed mammalian cells in both normoxia and hypoxia.Mol Syst Biol2013;9:712 PMCID:PMC3882799

[170] Durán RV,Robitaille AM.Glutaminolysis activates Rag-mTORC1 signaling.Mol Cell2012;47:349-58

[171] Metallo CM,Bell EL.Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.Nature2011;481:380-4 PMCID:PMC3710581

[172] Yoo HC,Nam M.A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells.Cell Metab2020;31:267-83.e12

[173] Ishak Gabra MB,Li H.Dietary glutamine supplementation suppresses epigenetically-activated oncogenic pathways to inhibit melanoma tumour growth.Nat Commun2020;11:3326 PMCID:PMC7335172

[174] Nakaya M,Zhou X.Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation.Immunity2014;40:692-705 PMCID:PMC4074507

[175] Sinclair LV,Emslie E,Taylor PM.Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation.Nat Immunol2013;14:500-8 PMCID:PMC3672957

[176] Carr EL,Wu GS.Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.J Immunol2010;185:1037-44 PMCID:PMC2897897

[177] Presnell SR,Durham J,Applegate A.Correction: differential fuel requirements of human NK cells and human CD8 T cells: glutamine regulates glucose uptake in strongly activated CD8 T cells.Immunohorizons2020;4:454

[178] Edwards DN,Raybuck AL.Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer.J Clin Invest2021;131:140100 PMCID:PMC7880417

[179] Wang W,Li N,Wu JH.Glutamine deprivation impairs function of infiltrating CD8⁺ T cells in hepatocellular carcinoma by inducing mitochondrial damage and apoptosis.World J Gastrointest Oncol2022;14:1124-40 PMCID:PMC9244988

[180] Nabe S,Suzuki J.Reinforce the antitumor activity of CD8⁺ T cells via glutamine restriction.Cancer Sci2018;109:3737-50 PMCID:PMC6272119

[181] Fu Q,Wang Y.Tumor-associated macrophage-derived interleukin-23 interlinks kidney cancer glutamine addiction with immune evasion.Eur Urol2019;75:752-63

[182] Ma G,Chen Y.Glutamine deprivation induces PD-L1 expression via activation of EGFR/ERK/c-Jun signaling in renal cancer.Mol Cancer Res2020;18:324-39

[183] Byun JK,Lee S.Inhibition of glutamine utilization synergizes with immune checkpoint inhibitor to promote antitumor immunity.Mol Cell2020;80:592-606.e8

[184] Leone RD,Englert JM.Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion.Science2019;366:1013-21 PMCID:PMC7023461

[185] Pons-Tostivint E,Fontenau JF,Bennouna J.STK11/LKB1 modulation of the immune response in lung cancer: from biology to therapeutic impact.Cells2021;10:3129 PMCID:PMC8618117

[186] Aggarwal C,Chien AL.Baseline plasma tumor mutation burden predicts response to pembrolizumab-based therapy in patients with metastatic non-small cell lung cancer.Clin Cancer Res2020;26:2354-61 PMCID:PMC7231655

[187] Biton J,Pécuchet N.TP53, STK11, and EGFR mutations predict tumor immune profile and the response to anti-PD-1 in lung adenocarcinoma.Clin Cancer Res2018;24:5710-23

[188] Skoulidis F,Greenawalt DM.STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma.Cancer Discov2018;8:822-35 PMCID:PMC6030433

[189] Best SA,Sethumadhavan S.Glutaminase inhibition impairs CD8 T cell activation in STK11-/Lkb1-deficient lung cancer.Cell Metab2022;34:874-87.e6

[190] Sanderson SM,Dai Z.Methionine metabolism in health and cancer: a nexus of diet and precision medicine.Nat Rev Cancer2019;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,Li J,Sun S.S-adenosylmethionine: a metabolite critical to the regulation of autophagy.Cell Prolif2020;53:e12891 PMCID:PMC7653241

[193] Froese DS,Baumgartner MR.Vitamin B₁₂, folate, and the methionine remethylation cycle - biochemistry, pathways, and regulation.J Inherit Metab Dis2019;42:673-85

[194] Lückerath K,Albert C.11C-Methionine-PET: a novel and sensitive tool for monitoring of early response to treatment in multiple myeloma.Oncotarget2015;6:8418-29 PMCID:PMC4480763

[195] Glaudemans AWJM,Heesters MAAM.Value of ¹¹C-methionine PET in imaging brain tumours and metastases.Eur J Nucl Med Mol Imaging2013;40:615-35

[196] Wang Z,Lee JHJ.Methionine is a metabolic dependency of tumor-initiating cells.Nat Med2019;25:825-37

[197] Zhao L,Liu X.mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A.Cell Biosci2022;12:183 PMCID:PMC9652997

[198] Ulanovskaya OA,Cravatt BF.NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink.Nat Chem Biol2013;9:300-6 PMCID:PMC3631284

[199] Sinclair LV,Brenes A.Antigen receptor control of methionine metabolism in T cells.eLife2019;8:e44210 PMCID:PMC6497464

[200] Hung MH,Ma C.Tumor methionine metabolism drives T-cell exhaustion in hepatocellular carcinoma.Nat Commun2021;12:1455 PMCID:PMC7935900

[201] Albers E.Metabolic characteristics and importance of the universal methionine salvage pathway recycling methionine from 5'-methylthioadenosine.IUBMB Life2009;61:1132-42

[202] Li T,Chen YX.Methionine deficiency facilitates antitumour immunity by altering m⁶A methylation of immune checkpoint transcripts.Gut2023;72:501-11 PMCID:PMC9933173

[203] Bian Y,Kremer DM.Cancer SLC43A2 alters T cell methionine metabolism and histone methylation.Nature2020;585:277-82 PMCID:PMC7486248

[204] Tripathi P,Wojciechowski S.STAT5 is critical to maintain effector CD8⁺ T cell responses.J Immunol2010;185:2116-24 PMCID:PMC2991082

[205] Xu S,Rodríguez-Morales P.Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8⁺ T cells in tumors.Immunity2021;54:1561-77.e7 PMCID:PMC9273026

[206] Zhang Y,Liu L.Enhancing CD8⁺ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy.Cancer Cell2017;32:377-91.e9 PMCID:PMC5751418

[207] Ma X,Lu Y.Cholesterol Induces CD8⁺ T cell exhaustion in the tumor microenvironment.Cell Metab2019;30:143-56.e5 PMCID:PMC7061417

[208] Mollinedo F.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 Res2020;61:611-35 PMCID:PMC7193951

[209] Ridker PM.LDL cholesterol: controversies and future therapeutic directions.Lancet2014;384:607-17

[210] Gelissen IC,Rye KA.ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I.Arterioscler Thromb Vasc Biol2006;26:534-40

[211] Cruz ALS,Fazolini NPB,Bozza PT.Lipid droplets: platforms with multiple functions in cancer hallmarks.Cell Death Dis2020;11:105 PMCID:PMC7005265

[212] Yue S,Lee SY.Cholesteryl ester accumulation induced by PTEN loss and PI3K/AKT activation underlies human prostate cancer aggressiveness.Cell Metab2014;19:393-406 PMCID:PMC3969850

[213] Antalis CJ,Rasool T,Buhman KK.High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation.Breast Cancer Res Treat2010;122:661-70

[214] Mayengbam SS,Pillai AD.Influence of cholesterol on cancer progression and therapy.Transl Oncol2021;14:101043 PMCID:PMC8010885

[215] Dong F,Eid W,Zha X.Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1.PLoS One2014;9:e113789 PMCID:PMC4240609

[216] Porstmann T,Griffiths B.SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth.Cell Metab2008;8:224-36 PMCID:PMC2593919

[217] Li J,Lee SS.Abrogating cholesterol esterification suppresses growth and metastasis of pancreatic cancer.Oncogene2016;35:6378-88 PMCID:PMC5093084

[218] Thysell E,Hörnberg E.Metabolomic characterization of human prostate cancer bone metastases reveals increased levels of cholesterol.PLoS One2010;5:e14175 PMCID:PMC2997052

[219] Lei K,Kaynak M.Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy.Nat Biomed Eng2021;5:1411-25 PMCID:PMC7612108

[220] Huang B,Xu C.Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities.Nat Metab2020;2:132-41

[221] Maxwell KN,Breslow JL.Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment.Proc Natl Acad Sci U S A2005;102:2069-74 PMCID:PMC546019

[222] Zhang DW,Garuti R.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 Chem2007;282:18602-12

[223] Lagace TA,Garuti R.Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice.J Clin Invest2006;116:2995-3005 PMCID:PMC1626117

[224] Poirier S,Poupon V.Dissection of the endogenous cellular pathways of PCSK9-induced low density lipoprotein receptor degradation: evidence for an intracellular route.J Biol Chem2009;284:28856-64 PMCID:PMC2781431

[225] Gu Y,Dong Y.PCSK9 facilitates melanoma pathogenesis via a network regulating tumor immunity.J Exp Clin Cancer Res2023;42:2 PMCID:PMC9806914

[226] Yuan J,Zheng X.Potentiating CD8⁺ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling.Protein Cell2021;12:240-60 PMCID:PMC8018994

[227] Liu X,Hu M.Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer.Nature2020;588:693-8 PMCID:PMC7770056

[228] Ni W,Liu Y.Targeting cholesterol biosynthesis promotes anti-tumor immunity by inhibiting long noncoding RNA SNHG29-mediated YAP activation.Mol Ther2021;29:2995-3010 PMCID:PMC8530930

[229] Lim WJ,Oh Y.Statins decrease programmed death-ligand 1 (PD-L1) by Inhibiting AKT and β-Catenin Signaling.Cells2021;10:2488 PMCID:PMC8472538

[230] Choe EJ,Bae JH,Park SS.Atorvastatin enhances the efficacy of immune checkpoint therapy and suppresses the cellular and extracellular vesicle PD-L1.Pharmaceutics2022;14:1660 PMCID:PMC9414447

[231] Wang Q,Shen L.Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs.Sci Adv2022;8:eabq4722 PMCID:PMC9417176

[232] Tatsuguchi T,Sugiura Y.Cancer-derived cholesterol sulfate is a key mediator to prevent tumor infiltration by effector T cells.Int Immunol2022;34:277-89 PMCID:PMC9020568

[233] Zech T,Gaus K.Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling.EMBO J2009;28:466-76 PMCID:PMC2657588

[234] Liu X,Sun X.Blocking cholesterol metabolism with tumor-penetrable nanovesicles to improve photodynamic cancer immunotherapy.Small Methods2023;7:2200898

[235] Lee IK,Kim H.RORα regulates cholesterol metabolism of CD8⁺ T cells for anticancer immunity.Cancers2020;12:1733 PMCID:PMC7407186

[236] Yang W,Xiong Y.Potentiating the antitumour response of CD8⁺ T cells by modulating cholesterol metabolism.Nature2016;531:651-5 PMCID:PMC4851431

[237] You W,Chen Y.SQLE, a key enzyme in cholesterol metabolism, correlates with tumor immune infiltration and immunotherapy outcome of pancreatic adenocarcinoma.Front Immunol2022;13:864244 PMCID:PMC9204319

[238] Furuhashi M.Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets.Nat Rev Drug Discov2008;7:489-503 PMCID:PMC2821027

[239] Guillou H,Martin PG.The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice.Prog Lipid Res2010;49:186-99

[240] Carracedo A,Pandolfi PP.Cancer metabolism: fatty acid oxidation in the limelight.Nat Rev Cancer2013;13:227-32 PMCID:PMC3766957

[241] Lou W,Ye Z.Lipid metabolic features of T cells in the tumor microenvironment.Lipids Health Dis2022;21:94 PMCID:PMC9535888

[242] Tomin T,Gindlhuber J.Deletion of adipose triglyceride lipase links triacylglycerol accumulation to a more-aggressive phenotype in A549 lung carcinoma cells.J Proteome Res2018;17:1415-25

[243] Snaebjornsson MT,Schulze A.Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer.Cell Metab2020;31:62-76

[244] Argilés JM,Stemmler B.Cancer cachexia: understanding the molecular basis.Nat Rev Cancer2014;14:754-62

[245] Nieman KM,Penicka CV.Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth.Nat Med2011;17:1498-503 PMCID:PMC4157349

[246] Wang YY,Milhas D.Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells.JCI Insight2017;2:e87489 PMCID:PMC5313068

[247] Ye H,Khan N.Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche.Cell Stem Cell2016;19:23-37 PMCID:PMC4938766

[248] Wen YA,Harris JW.Adipocytes activate mitochondrial fatty acid oxidation and autophagy to promote tumor growth in colon cancer.Cell Death Dis2017;8:e2593 PMCID:PMC5386470

[249] Ringel AE,Baker GJ.Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity.Cell2020;183:1848-66.e26 PMCID:PMC8064125

[250] Zhang C,Herrmann A.STAT3 activation-induced fatty acid oxidation in CD8⁺ T effector cells is critical for obesity-promoted breast tumor growth.Cell Metab2020;31:148-61.e5 PMCID:PMC6949402

[251] Patsoukis N,Chatterjee P.PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation.Nat Commun2015;6:6692 PMCID:PMC4389235

[252] Wang Z,Luna JI.Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.Nat Med2019;25:141-51 PMCID:PMC6324991

[253] Manzo T,Anderson KG.Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8⁺ T cells.J Exp Med2020;217:e20191920 PMCID:PMC7398173

[254] Huang SC,Ivanova Y.Cell-intrinsic lysosomal lipolysis is essential for alternative activation of macrophages.Nat Immunol2014;15:846-55 PMCID:PMC4139419

[255] Wang H,Tsui YC.CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors.Nat Immunol2020;21:298-308 PMCID:PMC7043937

[256] Yan D,Xu M.Lipid metabolic pathways confer the immunosuppressive function of myeloid-derived suppressor cells in tumor.Front Immunol2019;10:1399 PMCID:PMC6593140

[257] Hossain F,Wyczechowska D.Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies.Cancer Immunol Res2015;3:1236-47 PMCID:PMC4636942

[258] Auciello FR,Oon C.A stromal lysolipid-autotaxin signaling axis promotes pancreatic tumor progression.Cancer Discov2019;9:617-27 PMCID:PMC6497553

[259] Federico L,Vellano CP.Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression.J Lipid Res2016;57:25-35 PMCID:PMC4689343

[260] Matas-Rico E,van der Haar Àvila I.Autotaxin impedes anti-tumor immunity by suppressing chemotaxis and tumor infiltration of CD8⁺ T cells.Cell Rep2021;37:110013 PMCID:PMC8761359

[261] Mathew D,Strauch P,Pelanda R.LPA₅ is an inhibitory receptor that suppresses CD8 T-cell cytotoxic function via disruption of early TCR signaling.Front Immunol2019;10:1159 PMCID:PMC6558414

[262] Oda SK,Fujiwara Y.Lysophosphatidic acid inhibits CD8 T cell activation and control of tumor progression.Cancer Immunol Res2013;1:245-55 PMCID:PMC3893823

[263] Kremer KN,Thumkeo D.LPA suppresses T cell function by altering the cytoskeleton and disrupting immune synapse formation.Proc Natl Acad Sci U S A2022;119:e2118816119 PMCID:PMC9169816

[264] Turner JA,D’Antonio M.Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.Nat Commun2023;14:3214 PMCID:PMC10239450

[265] Deken M,Matas-rico E.922 A novel autotaxin inhibitor, IOA-289, modulates tumor, immune and stromal cell function and has monotherapy activity in fibrotic cancer models.J Immunother Cancer2021;9:A967

[266] Deken MA,Peyruchaud O.Characterization and translational development of IOA-289, a novel autotaxin inhibitor for the treatment of solid tumors.Immunooncol Technol2023;18:100384 PMCID:PMC10205783

[267] Xiong Q,Wang Z.Fatty acid synthase is the key regulator of fatty acid metabolism and is related to immunotherapy in bladder cancer.Front Immunol2022;13:836939 PMCID:PMC8982515

[268] Wang Q,Zhang W.Fatty acid synthase mutations predict favorable immune checkpoint inhibitor outcome and response in melanoma and non-small cell lung cancer patients.Cancers2022;14:5638 PMCID:PMC9688165

[269] Murphy WJ.The surprisingly positive association between obesity and cancer immunotherapy efficacy.JAMA2019;321:1247-8

[270] Woodall MJ,Campbell K,Young SL.The effects of obesity on anti-cancer immunity and cancer immunotherapy.Cancers2020;12:1230 PMCID:PMC7281442

[271] McQuade JL,Hess KR.Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.Lancet Oncol2018;19:310-22 PMCID:PMC5840029

[272] Cortellini A,Buti S.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 Cancer2019;7:57 PMCID:PMC6391761

[273] Diana A,D'Costa Z.Prognostic value, localization and correlation of PD-1/PD-L1, CD8 and FOXP3 with the desmoplastic stroma in pancreatic ductal adenocarcinoma.Oncotarget2016;7:40992-1004 PMCID:PMC5173037

[274] Shen T,Shen H.Prognostic value of programmed cell death protein 1 expression on CD8+ T lymphocytes in pancreatic cancer.Sci Rep2017;7:7848 PMCID:PMC5552822

[275] Winograd R,Evans RA.Induction of T-cell immunity overcomes complete resistance to PD-1 and CTLA-4 blockade and improves survival in pancreatic carcinoma.Cancer Immunol Res2015;3:399-411 PMCID:PMC4390506