{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:49Z","timestamp":1786121389010,"version":"build-2736575974"},"reference-count":204,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82270830"],"award-info":[{"award-number":["82270830"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82573420"],"award-info":[{"award-number":["82573420"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82270830"],"award-info":[{"award-number":["82270830"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82573420"],"award-info":[{"award-number":["82573420"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003819","name":"Natural Science Foundation of Hubei Province","doi-asserted-by":"crossref","award":["2023AFB870"],"award-info":[{"award-number":["2023AFB870"]}],"id":[{"id":"10.13039\/501100003819","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Metabolic reprogramming constitutes a fundamental hallmark of malignancy, orchestrating a hostile tumor microenvironment (TME) that severely compromises anti-tumor immunity. Despite the transformative success of immune checkpoint blockade and adoptive cell therapies, clinical efficacy is frequently curtailed by the metabolic barriers imposed by the TME. This review systematically elucidates the complex metabolic interplay between tumor cells and infiltrating T cells, highlighting two defining mechanisms driving immune evasion: the competitive sequestration of essential nutrients and the accumulation of immunosuppressive oncometabolites. We detail how the depletion of glucose and critical amino acids (glutamine, arginine, methionine, etc.) imposes a state of \u201cmetabolic siege\u201d on T cells, impairing their bioenergetics and effector functions. Concurrently, we explore how accumulated metabolites\u2014such as lactate, succinate, 2-hydroxyglutarate, kynurenine, and lipids\u2014function as non-canonical signaling molecules to subvert immune surveillance via epigenetic remodeling and oxidative stress. Furthermore, we synthesize emerging therapeutic strategies designed to dismantle this metabolic barrier, including targeting metabolic enzymes (IDO1 and FASN) and transporters, repurposing metabolic waste, and genetically engineering T cells with enhanced metabolic fitness and resilience. By integrating the latest insights into the \u201cmetabolism\u2013epigenetics\u2013immunity\u201d axis, this review provides a theoretical foundation for developing next-generation immunotherapies that target metabolic vulnerabilities to overcome resistance in cancer treatment.<\/jats:p>","DOI":"10.3390\/cells15151422","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T16:48:08Z","timestamp":1785948488000},"page":"1422","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic Bottlenecks and Opportunities: Reshaping the Tumor Microenvironment for Cancer Immunotherapy"],"prefix":"10.3390","volume":"15","author":[{"given":"Jianing","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"},{"name":"Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimei","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiran","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaying","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiexiao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ming","sequence":"additional","affiliation":[{"name":"Department of Breast and Thyroid Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s42255-020-00317-z","article-title":"Metabolites and the tumour microenvironment: From cellular mechanisms to systemic metabolism","volume":"3","author":"Elia","year":"2021","journal-title":"Nat. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.cmet.2023.06.003","article-title":"Beggars banquet: Metabolism in the tumor immune microenvironment and cancer therapy","volume":"35","author":"Zou","year":"2023","journal-title":"Cell Metab."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: Mechanisms and cutting-edge therapeutic approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1038\/s42255-020-0172-2","article-title":"We need to talk about the Warburg effect","volume":"2","author":"DeBerardinis","year":"2020","journal-title":"Nat. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.molcel.2019.10.023","article-title":"Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor","volume":"77","author":"Wu","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"216837","DOI":"10.1016\/j.canlet.2024.216837","article-title":"The emerging role of lactate in tumor microenvironment and its clinical relevance","volume":"590","author":"Chen","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1038\/s41392-023-01442-3","article-title":"Signaling pathways in cancer metabolism: Mechanisms and therapeutic targets","volume":"8","author":"You","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/s41577-021-00541-y","article-title":"Metabolic barriers to cancer immunotherapy","volume":"21","author":"DePeaux","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1038\/s41392-025-02334-4","article-title":"Targeting metabolic-epigenetic-immune axis in cancer: Molecular mechanisms and therapeutic implications","volume":"11","author":"Wang","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.semcancer.2024.03.001","article-title":"GLUT and HK: Two primary and essential key players in tumor glycolysis","volume":"100","author":"Yadav","year":"2024","journal-title":"Semin. Cancer Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1038\/s41586-021-03442-1","article-title":"Cell-programmed nutrient partitioning in the tumour microenvironment","volume":"593","author":"Reinfeld","year":"2021","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.cmet.2018.04.022","article-title":"Aerobic Glycolysis Controls Myeloid-Derived Suppressor Cells and Tumor Immunity via a Specific CEBPB Isoform in Triple-Negative Breast Cancer","volume":"28","author":"Li","year":"2018","journal-title":"Cell Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1016\/j.celrep.2018.01.040","article-title":"Early TCR Signaling Induces Rapid Aerobic Glycolysis Enabling Distinct Acute T Cell Effector Functions","volume":"22","author":"Menk","year":"2018","journal-title":"Cell Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1016\/j.cell.2015.08.016","article-title":"Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression","volume":"162","author":"Chang","year":"2015","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1038\/nature24057","article-title":"Glucose feeds the TCA cycle via circulating lactate","volume":"551","author":"Hui","year":"2017","journal-title":"Nature"},{"key":"ref_16","first-page":"228","article-title":"Lactate does not activate NF-\u03baB in oxidative tumor cells","volume":"6","author":"Cacace","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"102065","DOI":"10.1016\/j.redox.2021.102065","article-title":"Lactate and glutamine support NADPH generation in cancer cells under glucose deprived conditions","volume":"46","author":"Ying","year":"2021","journal-title":"Redox Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5301","DOI":"10.1158\/0008-5472.CAN-14-0319","article-title":"Cell surface lactate receptor GPR81 is crucial for cancer cell survival","volume":"74","author":"Roland","year":"2014","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3292","DOI":"10.1038\/s41388-020-1216-5","article-title":"The lactate receptor GPR81 promotes breast cancer growth via a paracrine mechanism involving antigen-presenting cells in the tumor microenvironment","volume":"39","author":"Brown","year":"2020","journal-title":"Oncogene"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.dnarep.2017.02.007","article-title":"Stimulation of lactate receptor (HCAR1) affects cellular DNA repair capacity","volume":"52","author":"Wagner","year":"2017","journal-title":"DNA Repair."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41586-020-03045-2","article-title":"Metabolic support of tumour-infiltrating regulatory T cells by lactic acid","volume":"591","author":"Watson","year":"2021","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.immuni.2024.01.019","article-title":"Lactate modulates RNA splicing to promote CTLA-4 expression in tumor-infiltrating regulatory T cells","volume":"57","author":"Ding","year":"2024","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1073\/pnas.1614035114","article-title":"Gpr132 sensing of lactate mediates tumor-macrophage interplay to promote breast cancer metastasis","volume":"114","author":"Chen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e26383","DOI":"10.4161\/onci.26383","article-title":"Tumor-derived lactate and myeloid-derived suppressor cells: Linking metabolism to cancer immunology","volume":"2","author":"Husain","year":"2013","journal-title":"Oncoimmunology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/j.cmet.2022.06.008","article-title":"Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8(+) T cells","volume":"34","author":"Elia","year":"2022","journal-title":"Cell Metab."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaan4631","DOI":"10.1126\/sciimmunol.aan4631","article-title":"Suppression of FIP200 and autophagy by tumor-derived lactate promotes na\u00efve T cell apoptosis and affects tumor immunity","volume":"2","author":"Xia","year":"2017","journal-title":"Sci. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.cmet.2016.08.011","article-title":"LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells","volume":"24","author":"Brand","year":"2016","journal-title":"Cell Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.3389\/fimmu.2019.02278","article-title":"NK Cell Metabolism and Tumor Microenvironment","volume":"10","author":"Orrantia","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1182\/blood-2005-05-1795","article-title":"Tumor-derived lactic acid modulates dendritic cell activation and antigen expression","volume":"107","author":"Gottfried","year":"2006","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1158\/0008-5472.CAN-17-1307","article-title":"Downregulation of Membrane Trafficking Proteins and Lactate Conditioning Determine Loss of Dendritic Cell Function in Lung Cancer","volume":"78","author":"Caronni","year":"2018","journal-title":"Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41467-019-13668-3","article-title":"Mitochondrial TCA cycle metabolites control physiology and disease","volume":"11","author":"Chandel","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1186\/s12929-022-00878-z","article-title":"Cancer-derived extracellular succinate: A driver of cancer metastasis","volume":"29","author":"Kuo","year":"2022","journal-title":"J. Biomed. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1186","DOI":"10.1086\/324413","article-title":"The R22X mutation of the SDHD gene in hereditary paraganglioma abolishes the enzymatic activity of complex II in the mitochondrial respiratory chain and activates the hypoxia pathway","volume":"69","author":"Favier","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4771","DOI":"10.1210\/jc.2002-020525","article-title":"Functional consequences of a SDHB gene mutation in an apparently sporadic pheochromocytoma","volume":"87","author":"Favier","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1007\/s12672-014-0172-3","article-title":"Succinate dehydrogenase subunit B mutations modify human neuroblastoma cell metabolism and proliferation","volume":"5","author":"Rapizzi","year":"2014","journal-title":"Horm. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e2106947118","DOI":"10.1073\/pnas.2106947118","article-title":"Functional succinate dehydrogenase deficiency is a common adverse feature of clear cell renal cancer","volume":"118","author":"Aggarwal","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ccr.2004.11.022","article-title":"Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase","volume":"7","author":"Selak","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nature11986","article-title":"Succinate is an inflammatory signal that induces IL-1\u03b2 through HIF-1\u03b1","volume":"496","author":"Tannahill","year":"2013","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1016\/j.bbamcr.2019.03.016","article-title":"The circadian protein CLOCK regulates cell metabolism via the mitochondrial carrier SLC25A10","volume":"1866","author":"Cai","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_41","first-page":"2526","article-title":"Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney","volume":"118","author":"Toma","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.semcdb.2019.04.013","article-title":"Regulation of succinate dehydrogenase and role of succinate in cancer","volume":"98","author":"Dando","year":"2020","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.pharmthera.2016.01.008","article-title":"Insight into SUCNR1 (GPR91) structure and function","volume":"159","author":"Gilissen","year":"2016","journal-title":"Pharmacol. Ther."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"109246","DOI":"10.1016\/j.celrep.2021.109246","article-title":"Extracellular succinate hyperpolarizes M2 macrophages through SUCNR1\/GPR91-mediated Gq signaling","volume":"35","author":"Trauelsen","year":"2021","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13174","DOI":"10.18632\/oncotarget.14485","article-title":"Oncometabolite succinate promotes angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation","volume":"8","author":"Mu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111193","DOI":"10.1016\/j.celrep.2022.111193","article-title":"Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation","volume":"40","author":"Gudgeon","year":"2022","journal-title":"Cell Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"eabm8161","DOI":"10.1126\/sciimmunol.abm8161","article-title":"Succinate dehydrogenase\/complex II is critical for metabolic and epigenetic regulation of T cell proliferation and inflammation","volume":"7","author":"Chen","year":"2022","journal-title":"Sci. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s42255-018-0014-7","article-title":"Coupling Krebs cycle metabolites to signalling in immunity and cancer","volume":"1","author":"Ryan","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1002\/path.2932","article-title":"Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status","volume":"225","author":"Bardella","year":"2011","journal-title":"J. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/nature19353","article-title":"Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition","volume":"537","author":"Sciacovelli","year":"2016","journal-title":"Nature"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ccr.2011.09.006","article-title":"Renal cyst formation in Fh1-deficient mice is independent of the Hif\/Phd pathway: Roles for fumarate in KEAP1 succination and Nrf2 signaling","volume":"20","author":"Adam","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1196\/annals.1433.047","article-title":"Succination of proteins by fumarate: Mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetes","volume":"1126","author":"Blatnik","year":"2008","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1038\/nchembio.495","article-title":"Identification of lysine succinylation as a new post-translational modification","volume":"7","author":"Zhang","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/S0190-9622(89)70071-2","article-title":"Systemic therapy with fumaric acid derivates: New possibilities in the treatment of psoriasis","volume":"20","author":"Nieboer","year":"1989","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e60","DOI":"10.1016\/j.jaad.2013.10.031","article-title":"Management of psoriasis vulgaris and multiple sclerosis with fumaric acid","volume":"70","author":"Gkalpakiotis","year":"2014","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1038\/s41422-018-0045-3","article-title":"Dimethyl fumarate: Targeting glycolysis to treat MS","volume":"28","author":"Angiari","year":"2018","journal-title":"Cell Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3354","DOI":"10.1016\/j.molcel.2024.07.021","article-title":"Malic enzyme 2 maintains metabolic state and anti-tumor immunity of CD8(+) T cells","volume":"84","author":"Zhang","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1016\/j.cmet.2023.04.017","article-title":"Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8(+) T cells in the tumor microenvironment","volume":"35","author":"Cheng","year":"2023","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1016\/j.cmet.2015.06.023","article-title":"Hypoxia Induces Production of L-2-Hydroxyglutarate","volume":"22","author":"Intlekofer","year":"2015","journal-title":"Cell Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5381","DOI":"10.1158\/1078-0432.CCR-17-3855","article-title":"D-2-Hydroxyglutarate Is an Intercellular Mediator in IDH-Mutant Gliomas Inhibiting Complement and T Cells","volume":"24","author":"Zhang","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1038\/s41591-018-0095-6","article-title":"Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate","volume":"24","author":"Bunse","year":"2018","journal-title":"Nat. Med."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1126\/science.abj5104","article-title":"Oncometabolite d-2HG alters T cell metabolism to impair CD8(+) T cell function","volume":"377","author":"Notarangelo","year":"2022","journal-title":"Science"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/nature23475","article-title":"Metabolic control of T(H)17 and induced T(reg) cell balance by an epigenetic mechanism","volume":"548","author":"Xu","year":"2017","journal-title":"Nature"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1806662","DOI":"10.1080\/2162402X.2020.1806662","article-title":"IDH-mutant gliomas harbor fewer regulatory T cells in humans and mice","volume":"9","author":"Richardson","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1038\/nature20165","article-title":"S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate","volume":"540","author":"Tyrakis","year":"2016","journal-title":"Nature"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"4483","DOI":"10.1182\/bloodadvances.2020002309","article-title":"The S enantiomer of 2-hydroxyglutarate increases central memory CD8 populations and improves CAR-T therapy outcome","volume":"4","author":"Foskolou","year":"2020","journal-title":"Blood Adv."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"113013","DOI":"10.1016\/j.celrep.2023.113013","article-title":"The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function","volume":"42","author":"Foskolou","year":"2023","journal-title":"Cell Rep."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.trecan.2021.06.003","article-title":"IDH-Mutant Brain Tumors Hit the Achilles\u2019 Heel of Macrophages with R-2-Hydroxyglutarate","volume":"7","year":"2021","journal-title":"Trends Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1352165","DOI":"10.3389\/fimmu.2024.1352165","article-title":"Control of immune cell signaling by the immuno-metabolite itaconate","volume":"15","author":"Lang","year":"2024","journal-title":"Front. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41577-019-0128-5","article-title":"Itaconate: The poster child of metabolic reprogramming in macrophage function","volume":"19","author":"Artyomov","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature25986","article-title":"Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1","volume":"556","author":"Mills","year":"2018","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"12673","DOI":"10.1021\/jacs.3c02332","article-title":"Discovery of Itaconate-Mediated Lysine Acylation","volume":"145","author":"Liu","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.3892\/or.2014.3474","article-title":"Immune responsive gene 1, a novel oncogene, increases the growth and tumorigenicity of glioma","volume":"32","author":"Pan","year":"2014","journal-title":"Oncol. Rep."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s11658-023-00503-3","article-title":"Metabolite itaconate in host immunoregulation and defense","volume":"28","author":"Yang","year":"2023","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"eadg0654","DOI":"10.1126\/sciadv.adg0654","article-title":"Targeting IRG1 reverses the immunosuppressive function of tumor-associated macrophages and enhances cancer immunotherapy","volume":"9","author":"Chen","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1172\/JCI99169","article-title":"Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors","volume":"128","author":"Weiss","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.1038\/s42255-022-00676-9","article-title":"Myeloid-derived itaconate suppresses cytotoxic CD8(+) T cells and promotes tumour growth","volume":"4","author":"Zhao","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e160463","DOI":"10.1172\/JCI160463","article-title":"The immunometabolite itaconate stimulates OXGR1 to promote mucociliary clearance during the pulmonary innate immune response","volume":"133","author":"Zeng","year":"2023","journal-title":"J. Clin. Investig."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1124\/pr.112.007179","article-title":"International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: Recommendations for new pairings with cognate ligands","volume":"65","author":"Davenport","year":"2013","journal-title":"Pharmacol. Rev."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/bs.ai.2019.04.002","article-title":"Roles of cysteinyl leukotrienes and their receptors in immune cell-related functions","volume":"142","author":"Kanaoka","year":"2019","journal-title":"Adv. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1158\/0008-5472.CAN-14-2211","article-title":"Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein","volume":"75","author":"Kamphorst","year":"2015","journal-title":"Cancer Res."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature12138","article-title":"Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells","volume":"497","author":"Commisso","year":"2013","journal-title":"Nature"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1016\/j.molcel.2020.09.006","article-title":"Amino Acids and Their Transporters in T Cell Immunity and Cancer Therapy","volume":"80","author":"Wang","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1186\/s13046-023-02845-4","article-title":"Amino acid metabolism reprogramming: Shedding new light on T cell anti-tumor immunity","volume":"42","author":"Zheng","year":"2023","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.drudis.2016.12.003","article-title":"Targeting amino acid metabolism for cancer therapy","volume":"22","author":"Lukey","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.cell.2017.03.023","article-title":"Physiologic Medium Rewires Cellular Metabolism and Reveals Uric Acid as an Endogenous Inhibitor of UMP Synthase","volume":"169","author":"Cantor","year":"2017","journal-title":"Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.trecan.2017.01.005","article-title":"Glutamine Metabolism in Cancer: Understanding the Heterogeneity","volume":"3","author":"Cluntun","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Scalise, M., Pochini, L., Galluccio, M., Console, L., and Indiveri, C. (2017). Glutamine Transport and Mitochondrial Metabolism in Cancer Cell Growth. Front. Oncol., 7.","DOI":"10.3389\/fonc.2017.00306"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e31349","DOI":"10.1002\/jcp.31349","article-title":"Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy","volume":"239","author":"Zhang","year":"2024","journal-title":"J. Cell. Physiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1016\/j.immuni.2014.04.007","article-title":"Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation","volume":"40","author":"Nakaya","year":"2014","journal-title":"Immunity"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1016\/j.cell.2018.10.001","article-title":"Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism","volume":"175","author":"Johnson","year":"2018","journal-title":"Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.4049\/jimmunol.0903586","article-title":"Glutamine uptake and metabolism are coordinately regulated by ERK\/MAPK during T lymphocyte activation","volume":"185","author":"Carr","year":"2010","journal-title":"J. Immunol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2025s","DOI":"10.1093\/jn\/138.10.2025S","article-title":"Nonnutritive effects of glutamine","volume":"138","author":"Roth","year":"2008","journal-title":"J. Nutr."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.4049\/jimmunol.1501756","article-title":"Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties","volume":"196","author":"Metzler","year":"2016","journal-title":"J. Immunol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"ra97","DOI":"10.1126\/scisignal.aab2610","article-title":"Glutamine-dependent \u03b1-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation","volume":"8","author":"Klysz","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1126\/science.aav2588","article-title":"Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion","volume":"366","author":"Leone","year":"2019","journal-title":"Science"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1002\/jcp.1041240216","article-title":"The essential role of L-glutamine in lymphocyte differentiation in vitro","volume":"124","author":"Crawford","year":"1985","journal-title":"J. Cell. Physiol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Cruzat, V., Macedo Rogero, M., Noel Keane, K., Curi, R., and Newsholme, P. (2018). Glutamine: Metabolism and Immune Function, Supplementation and Clinical Translation. Nutrients, 10.","DOI":"10.20944\/preprints201809.0459.v1"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"508s","DOI":"10.1093\/ajcn\/83.2.508S","article-title":"Arginine: Beyond protein","volume":"83","author":"Morris","year":"2006","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1756-8722-1-14","article-title":"Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma","volume":"1","author":"Tate","year":"2008","journal-title":"J. Hematol. Oncol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1568","DOI":"10.1182\/blood-2006-06-031856","article-title":"L-arginine availability regulates T-lymphocyte cell-cycle progression","volume":"109","author":"Rodriguez","year":"2007","journal-title":"Blood"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1038\/s41568-019-0106-z","article-title":"Immune control by amino acid catabolism during tumorigenesis and therapy","volume":"19","author":"Lemos","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"5303","DOI":"10.1007\/s00018-021-03828-4","article-title":"Arginine-dependent immune responses","volume":"78","author":"Reith","year":"2021","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"129607","DOI":"10.1016\/j.ijbiomac.2024.129607","article-title":"A comprehensive review on signaling attributes of serine and serine metabolism in health and disease","volume":"260","author":"Wu","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40170-018-0191-6","article-title":"p53-Mediated Adaptation To Serine Starvation is retained by a common tumour-derived mutant","volume":"6","author":"Humpton","year":"2018","journal-title":"Cancer Metab."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/ng.890","article-title":"Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis","volume":"43","author":"Locasale","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1475","DOI":"10.1038\/ng.3421","article-title":"NRF2 regulates serine biosynthesis in non-small cell lung cancer","volume":"47","author":"DeNicola","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/s42255-019-0108-x","article-title":"Cellular redox state constrains serine synthesis and nucleotide production to impact cell proliferation","volume":"1","author":"Diehl","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1038\/nature11743","article-title":"Serine starvation induces stress and p53-dependent metabolic remodelling in cancer cells","volume":"493","author":"Maddocks","year":"2013","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1038\/nature22056","article-title":"Modulating the therapeutic response of tumours to dietary serine and glycine starvation","volume":"544","author":"Maddocks","year":"2017","journal-title":"Nature"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.cmet.2016.06.007","article-title":"Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation","volume":"24","author":"Santos","year":"2016","journal-title":"Cell Metab."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.cmet.2017.01.014","article-title":"Serine Is an Essential Metabolite for Effector T Cell Expansion","volume":"25","author":"Ma","year":"2017","journal-title":"Cell Metab."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.cmet.2020.03.004","article-title":"Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function","volume":"31","author":"Kurniawan","year":"2020","journal-title":"Cell Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"eaaf9794","DOI":"10.1126\/science.aaf9794","article-title":"Kynurenines: Tryptophan\u2019s metabolites in exercise, inflammation, and mental health","volume":"357","author":"Cervenka","year":"2017","journal-title":"Science"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41573-019-0016-5","article-title":"Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond","volume":"18","author":"Platten","year":"2019","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1126\/science.1073514","article-title":"Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase","volume":"297","author":"Munn","year":"2002","journal-title":"Science"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.4049\/jimmunol.176.11.6752","article-title":"The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells","volume":"176","author":"Fallarino","year":"2006","journal-title":"J. Immunol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"5435","DOI":"10.1158\/0008-5472.CAN-12-0569","article-title":"Tryptophan catabolism in cancer: Beyond IDO and tryptophan depletion","volume":"72","author":"Platten","year":"2012","journal-title":"Cancer Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"e148549","DOI":"10.1172\/JCI148549","article-title":"Fighting in a wasteland: Deleterious metabolites and antitumor immunity","volume":"132","author":"Watson","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.3389\/fimmu.2017.01360","article-title":"Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?","volume":"8","author":"Mellor","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.cels.2017.12.014","article-title":"A Landscape of Metabolic Variation across Tumor Types","volume":"6","author":"Reznik","year":"2018","journal-title":"Cell Syst."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1074\/jbc.RA117.000631","article-title":"Trace derivatives of kynurenine potently activate the aryl hydrocarbon receptor (AHR)","volume":"293","author":"Seok","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/nature06471","article-title":"Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease","volume":"451","author":"Romani","year":"2008","journal-title":"Nature"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ccell.2018.02.005","article-title":"Tumor-Repopulating Cells Induce PD-1 Expression in CD8(+) T Cells by Transferring Kynurenine and AhR Activation","volume":"33","author":"Liu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"19961","DOI":"10.1073\/pnas.1014465107","article-title":"Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism","volume":"107","author":"Nguyen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1084\/jem.20020121","article-title":"Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase","volume":"196","author":"Frumento","year":"2002","journal-title":"J. Exp. Med."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1038\/nature10491","article-title":"An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor","volume":"478","author":"Opitz","year":"2011","journal-title":"Nature"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1038\/sj.cdd.4401073","article-title":"T cell apoptosis by tryptophan catabolism","volume":"9","author":"Fallarino","year":"2002","journal-title":"Cell Death Differ."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"103779","DOI":"10.1016\/j.ebiom.2021.103779","article-title":"T cell fat catabolism: A novel target for kynurenine?","volume":"75","author":"Puccetti","year":"2022","journal-title":"EBioMedicine"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.tem.2024.05.010","article-title":"One-carbon metabolism shapes T cell immunity in cancer","volume":"35","author":"Qiu","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"400","DOI":"10.1016\/j.tem.2024.01.009","article-title":"Dietary methionine restriction in cancer development and antitumor immunity","volume":"35","author":"Ji","year":"2024","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"e44210","DOI":"10.7554\/eLife.44210","article-title":"Antigen receptor control of methionine metabolism in T cells","volume":"8","author":"Sinclair","year":"2019","journal-title":"Elife"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41586-020-2682-1","article-title":"Cancer SLC43A2 alters T cell methionine metabolism and histone methylation","volume":"585","author":"Bian","year":"2020","journal-title":"Nature"},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1002\/JLB.2RI0717-278R","article-title":"Biology of IL-2 and its therapeutic modulation: Mechanisms and strategies","volume":"103","author":"Mitra","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1016\/j.tips.2024.03.002","article-title":"Targeting methionine metabolism in cancer: Opportunities and challenges","volume":"45","author":"Bin","year":"2024","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_137","doi-asserted-by":"crossref","unstructured":"Castellano, F., and Molinier-Frenkel, V. (2020). Control of T-Cell Activation and Signaling by Amino-Acid Catabolizing Enzymes. Front. Cell Dev. Biol., 8.","DOI":"10.3389\/fcell.2020.613416"},{"key":"ref_138","doi-asserted-by":"crossref","unstructured":"Mehdi, A., Attias, M., Mahmood, N., Arakelian, A., Mihalcioiu, C., Piccirillo, C.A., Szyf, M., and Rabbani, S.A. (2020). Enhanced Anticancer Effect of a Combination of S-adenosylmethionine (SAM) and Immune Checkpoint Inhibitor (ICPi) in a Syngeneic Mouse Model of Advanced Melanoma. Front. Oncol., 10.","DOI":"10.3389\/fonc.2020.01361"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"101055","DOI":"10.1016\/j.plipres.2020.101055","article-title":"Lipids in the tumor microenvironment: From cancer progression to treatment","volume":"80","author":"Corn","year":"2020","journal-title":"Prog. Lipid Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"188984","DOI":"10.1016\/j.bbcan.2023.188984","article-title":"Dietary fat and lipid metabolism in the tumor microenvironment","volume":"1878","author":"Goswami","year":"2023","journal-title":"Biochim Biophys. Acta Rev. Cancer"},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41416-019-0650-z","article-title":"Reprogramming of fatty acid metabolism in cancer","volume":"122","author":"Koundouros","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1186\/s13045-023-01498-2","article-title":"Lipid metabolic reprogramming in tumor microenvironment: From mechanisms to therapeutics","volume":"16","author":"Jin","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40170-016-0163-7","article-title":"Adipocyte lipolysis links obesity to breast cancer growth: Adipocyte-derived fatty acids drive breast cancer cell proliferation and migration","volume":"5","author":"Balaban","year":"2017","journal-title":"Cancer Metab."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s12964-018-0221-6","article-title":"Utilization of adipocyte-derived lipids and enhanced intracellular trafficking of fatty acids contribute to breast cancer progression","volume":"16","author":"Yang","year":"2018","journal-title":"Cell Commun. Signal."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1016\/S0006-291X(03)00265-1","article-title":"Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains","volume":"302","author":"Swinnen","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.yexcr.2013.10.016","article-title":"Fatty acid synthase plays a role in cancer metabolism beyond providing fatty acids for phospholipid synthesis or sustaining elevations in glycolytic activity","volume":"320","author":"Hopperton","year":"2014","journal-title":"Exp. Cell Res."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1194\/jlr.M500151-JLR200","article-title":"Free fatty acid release from human breast cancer tissue inhibits cytotoxic T-lymphocyte-mediated killing","volume":"46","author":"Kleinfeld","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"1848","DOI":"10.1016\/j.cell.2020.11.009","article-title":"Obesity Shapes Metabolism in the Tumor Microenvironment to Suppress Anti-Tumor Immunity","volume":"183","author":"Ringel","year":"2020","journal-title":"Cell"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.cmet.2019.10.013","article-title":"STAT3 Activation-Induced Fatty Acid Oxidation in CD8(+) T Effector Cells Is Critical for Obesity-Promoted Breast Tumor Growth","volume":"31","author":"Zhang","year":"2020","journal-title":"Cell Metab."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.ccell.2017.08.004","article-title":"Enhancing CD8(+) T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy","volume":"32","author":"Zhang","year":"2017","journal-title":"Cancer Cell"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1158\/2326-6066.CIR-18-0095","article-title":"PPAR-Induced Fatty Acid Oxidation in T Cells Increases the Number of Tumor-Reactive CD8(+) T Cells and Facilitates Anti-PD-1 Therapy","volume":"6","author":"Chowdhury","year":"2018","journal-title":"Cancer Immunol. Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1016\/j.immuni.2021.05.003","article-title":"Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors","volume":"54","author":"Xu","year":"2021","journal-title":"Immunity"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"e20191920","DOI":"10.1084\/jem.20191920","article-title":"Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8+ T cells","volume":"217","author":"Manzo","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nm.2172","article-title":"Lipid accumulation and dendritic cell dysfunction in cancer","volume":"16","author":"Herber","year":"2010","journal-title":"Nat. Med."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"1330","DOI":"10.1038\/s41590-018-0251-7","article-title":"Metabolic reprogramming of natural killer cells in obesity limits antitumor responses","volume":"19","author":"Michelet","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1038\/s41590-019-0589-5","article-title":"CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors","volume":"21","author":"Wang","year":"2020","journal-title":"Nat. Immunol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1158\/0008-5472.CAN-19-2994","article-title":"Enhanced Lipid Accumulation and Metabolism Are Required for the Differentiation and Activation of Tumor-Associated Macrophages","volume":"80","author":"Su","year":"2020","journal-title":"Cancer Res."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/s41586-019-1118-2","article-title":"Fatty acid transport protein 2 reprograms neutrophils in cancer","volume":"569","author":"Veglia","year":"2019","journal-title":"Nature"},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1038\/s41467-018-07505-2","article-title":"Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression","volume":"9","author":"Rice","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1038\/s41577-024-01026-4","article-title":"Cancer cell metabolism and antitumour immunity","volume":"24","author":"Rathmell","year":"2024","journal-title":"Nat. Rev. Immunol."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.cmet.2018.02.024","article-title":"Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy","volume":"27","author":"Cascone","year":"2018","journal-title":"Cell Metab."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nchembio.2143","article-title":"Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition","volume":"12","author":"Boudreau","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1038\/s41418-023-01157-6","article-title":"LncRNA GLTC targets LDHA for succinylation and enzymatic activity to promote progression and radioiodine resistance in papillary thyroid cancer","volume":"30","author":"Shi","year":"2023","journal-title":"Cell Death Differ."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1186\/s12967-021-02825-2","article-title":"Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer: From bedside to bench","volume":"19","author":"Yang","year":"2021","journal-title":"J. Transl. Med."},{"key":"ref_165","doi-asserted-by":"crossref","unstructured":"Renner, O., Mayer, M., Leischner, C., Burkard, M., Berger, A., Lauer, U.M., Venturelli, S., and Bischoff, S.C. (2022). Systematic Review of Gossypol\/AT-101 in Cancer Clinical Trials. Pharmaceuticals, 15.","DOI":"10.3390\/ph15020144"},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.3324\/haematol.2016.163030","article-title":"Inhibition of monocarboxyate transporter 1 by AZD3965 as a novel therapeutic approach for diffuse large B-cell lymphoma and Burkitt lymphoma","volume":"102","author":"Noble","year":"2017","journal-title":"Haematologica"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/cns.12362","article-title":"Inhibition of G protein-coupled receptor 81 (GPR81) protects against ischemic brain injury","volume":"21","author":"Shen","year":"2015","journal-title":"CNS Neurosci. Ther."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1038\/s41590-023-01738-0","article-title":"Lithium carbonate revitalizes tumor-reactive CD8(+) T cells by shunting lactic acid into mitochondria","volume":"25","author":"Ma","year":"2024","journal-title":"Nat. Immunol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"9214","DOI":"10.1039\/D3NR01052J","article-title":"Dual-inhibition of lactate metabolism and Prussian blue-mediated radical generation for enhanced chemodynamic therapy and antimetastatic effect","volume":"15","author":"Li","year":"2023","journal-title":"Nanoscale"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00424-013-1369-y","article-title":"Sodium-coupled dicarboxylate and citrate transporters from the SLC13 family","volume":"466","author":"Pajor","year":"2014","journal-title":"Pflug. Arch."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"3596","DOI":"10.1016\/j.bmcl.2011.04.091","article-title":"Discovery of a potent and selective small molecule hGPR91 antagonist","volume":"21","author":"Bhuniya","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1038\/nature10363","article-title":"Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase","volume":"477","author":"Frezza","year":"2011","journal-title":"Nature"},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1056\/NEJMoa2117344","article-title":"Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia","volume":"386","author":"Montesinos","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1038\/s41591-022-02141-2","article-title":"Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: A randomized, perioperative phase 1 trial","volume":"29","author":"Mellinghoff","year":"2023","journal-title":"Nat. Med."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1016\/j.ymthe.2022.01.007","article-title":"D2HGDH-mediated D2HG catabolism enhances the anti-tumor activities of CAR-T cells in an immunosuppressive microenvironment","volume":"30","author":"Yang","year":"2022","journal-title":"Mol. Ther."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1038\/s42255-022-00577-x","article-title":"Citraconate inhibits ACOD1 (IRG1) catalysis, reduces interferon responses and oxidative stress, and modulates inflammation and cell metabolism","volume":"4","author":"Chen","year":"2022","journal-title":"Nat. Metab."},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1053\/j.gastro.2021.08.030","article-title":"Hepatic miR-144 Drives Fumarase Activity Preventing NRF2 Activation During Obesity","volume":"161","author":"Azzimato","year":"2021","journal-title":"Gastroenterology"},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"LB-085","DOI":"10.1158\/1538-7445.AM2016-LB-085","article-title":"Abstract LB-085: RG70099: A novel, highly potent dual IDO1\/TDO inhibitor to reverse metabolic suppression of immune cells in the tumor micro-environment","volume":"76","author":"Gyulveszi","year":"2016","journal-title":"Cancer Res."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1038\/nbt.4180","article-title":"Reversal of indoleamine 2,3-dioxygenase-mediated cancer immune suppression by systemic kynurenine depletion with a therapeutic enzyme","volume":"36","author":"Triplett","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s41392-022-01099-4","article-title":"Discovery of a mammalian FASN inhibitor against xenografts of non-small cell lung cancer and melanoma","volume":"7","author":"Cao","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1016\/j.ebiom.2015.06.020","article-title":"Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression","volume":"2","author":"Ventura","year":"2015","journal-title":"EBioMedicine"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"35784","DOI":"10.1038\/srep35784","article-title":"Monoacylglycerol Lipase: A Novel Potential Therapeutic Target and Prognostic Indicator for Hepatocellular Carcinoma","volume":"6","author":"Zhang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"1001","DOI":"10.1016\/j.cmet.2021.02.015","article-title":"CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability","volume":"33","author":"Ma","year":"2021","journal-title":"Cell Metab."},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/S1470-2045(19)30274-8","article-title":"Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301\/KEYNOTE-252): A phase 3, randomised, double-blind study","volume":"20","author":"Long","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00281-018-0702-0","article-title":"Inhibiting IDO pathways to treat cancer: Lessons from the ECHO-301 trial and beyond","volume":"41","author":"Muller","year":"2019","journal-title":"Semin. Immunopathol."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1158\/1535-7163.MCT-20-0430","article-title":"The Glutaminase Inhibitor CB-839 (Telaglenastat) Enhances the Antimelanoma Activity of T-Cell-Mediated Immunotherapies","volume":"20","author":"Varghese","year":"2021","journal-title":"Mol. Cancer Ther."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.hbpd.2025.12.018","article-title":"Cost-effectiveness of ivosidenib in patients with previously treated isocitrate dehydrogenase 1 (IDH1)-mutant cholangiocarcinoma: An Italian perspective","volume":"25","author":"Giuliani","year":"2026","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1016\/j.cell.2015.07.022","article-title":"A Call for Systematic Research on Solute Carriers","volume":"162","author":"Snijder","year":"2015","journal-title":"Cell"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cmet.2014.05.004","article-title":"The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function","volume":"20","author":"Macintyre","year":"2014","journal-title":"Cell Metab."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.ccr.2005.09.008","article-title":"ATP citrate lyase inhibition can suppress tumor cell growth","volume":"8","author":"Hatzivassiliou","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"E2","DOI":"10.1038\/s41586-019-1490-y","article-title":"Author Correction: Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function","volume":"573","author":"Bailis","year":"2019","journal-title":"Nature"},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"1217","DOI":"10.1016\/j.cell.2015.08.012","article-title":"Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses","volume":"162","author":"Ho","year":"2015","journal-title":"Cell"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"3737","DOI":"10.1111\/cas.13827","article-title":"Reinforce the antitumor activity of CD8(+) T cells via glutamine restriction","volume":"109","author":"Nabe","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"303ra139","DOI":"10.1126\/scitranslmed.aac5415","article-title":"Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia","volume":"7","author":"Porter","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"4479","DOI":"10.1172\/JCI69589","article-title":"Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function","volume":"123","author":"Sukumar","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.cmet.2023.12.010","article-title":"Mitochondrial isocitrate dehydrogenase impedes CAR T cell function by restraining antioxidant metabolism and histone acetylation","volume":"36","author":"Si","year":"2024","journal-title":"Cell Metab."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.cmet.2022.03.013","article-title":"The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function","volume":"34","author":"Wenes","year":"2022","journal-title":"Cell Metab."},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"eaaz6314","DOI":"10.1126\/scitranslmed.aaz6314","article-title":"Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy","volume":"13","author":"Liu","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1038\/s41573-025-01227-z","article-title":"Metabolites as agents and targets for cancer immunotherapy","volume":"24","author":"Trefny","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41568-024-00786-4","article-title":"Metabolic interplays between the tumour and the host shape the tumour macroenvironment","volume":"25","author":"Janowitz","year":"2025","journal-title":"Nat. Rev. Cancer"},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"153101","DOI":"10.1016\/j.bbrc.2025.153101","article-title":"Integrating biochemical and computational approaches to identify targeted therapeutic strategies for liver fibrosis: Effects of Telaglenastat (CB-839) on the glutaminase pathway","volume":"795","author":"Fakher","year":"2026","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/j.molcel.2020.05.034","article-title":"Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy","volume":"78","author":"Bader","year":"2020","journal-title":"Mol. Cell"},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/mas.21804","article-title":"Advances in mass spectrometry imaging for spatial cancer metabolomics","volume":"43","author":"Ma","year":"2024","journal-title":"Mass Spectrom. Rev."},{"key":"ref_204","doi-asserted-by":"crossref","unstructured":"Hilovsky, D., Hartsell, J., Young, J.D., and Liu, X. (2024). Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies. 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