{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T01:51:23Z","timestamp":1792633883691,"version":"4.5.0"},"reference-count":60,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1CA226983-04"],"award-info":[{"award-number":["RO1CA226983-04"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.<\/jats:p>","DOI":"10.3390\/antib10030025","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T02:05:37Z","timestamp":1624845937000},"page":"25","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer"],"prefix":"10.3390","volume":"10","author":[{"given":"Violet Y.","family":"Tu","sequence":"first","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Biological Physics, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asma","family":"Ayari","sequence":"additional","affiliation":[{"name":"Nucleus Biologics, LLC., San Diego, CA 92127, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roddy S.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Center for Cellular Immunotherapies, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.1038\/onc.2008.271","article-title":"The tumor microenvironment and its role in promoting tumor growth","volume":"27","author":"Whiteside","year":"2008","journal-title":"Oncogene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2527","DOI":"10.1002\/ijc.26031","article-title":"The seed and soil hypothesis revisited-The role of tumor-stroma interactions in metastasis to different organs","volume":"128","author":"Langley","year":"2011","journal-title":"Int. J. Cancer"},{"key":"ref_3","first-page":"98","article-title":"The distribution of secondary growths in cancer of the breast","volume":"8","author":"Paget","year":"1989","journal-title":"Cancer Metastasis Rev."},{"key":"ref_4","first-page":"1928","article-title":"Metastatic behavior of tumor cells isolated from primary and metastatic human colorectal carcinomas implanted into different sites in nude mice","volume":"46","author":"Giavazzi","year":"1986","journal-title":"Cancer Res."},{"key":"ref_5","first-page":"4109","article-title":"Growth and metastasis of tumor cells isolated from a human renal cell carcinoma implanted into different organs of nude mice","volume":"46","author":"Naito","year":"1986","journal-title":"Cancer Res."},{"key":"ref_6","first-page":"1561","article-title":"Demonstration of resistance against methylcholanthrene-induced sarcomas in the primary autochthonous host","volume":"20","author":"Klein","year":"1960","journal-title":"Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.tibs.2015.12.001","article-title":"The Warburg Effect: How Does it Benefit Cancer Cells?","volume":"41","author":"Liberti","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1042\/bj0230536","article-title":"Observations on the carbohydrate metabolism of tumours","volume":"23","author":"Crabtree","year":"1929","journal-title":"Biochem. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1038\/jcbfm.2011.175","article-title":"Brain lactate metabolism: The discoveries and the controversies","volume":"32","author":"Dienel","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Brooks, G.A., Arevalo, J.A., Osmond, A.D., Leija, R.G., Curl, C.C., and Tovar, A.P. (2021). Lactate in contemporary biology: A phoenix risen. J. Physiol.","DOI":"10.1113\/JP280955"},{"key":"ref_11","first-page":"3930","article-title":"Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice","volume":"118","author":"Sonveaux","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_12","first-page":"115","article-title":"Glucose feeds the TCA cycle via circulating lactate","volume":"551","author":"Hui","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_13","first-page":"424","article-title":"Interplay between metabolic identities in the intestinal crypt supports stem cell function","volume":"543","author":"Schewe","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_14","first-page":"645","article-title":"Metabolic support of tumour-infiltrating regulatory T cells by lactic acid","volume":"591","author":"Watson","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cmet.2016.12.018","article-title":"Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments","volume":"25","author":"Angelin","year":"2017","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1158\/jcr.1925.148","article-title":"The Metabolism of Carcinoma Cells","volume":"9","author":"Warburg","year":"1925","journal-title":"J. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2482","DOI":"10.1158\/1078-0432.CCR-17-3070","article-title":"Oxidative Phosphorylation as an Emerging Target in Cancer Therapy","volume":"24","author":"Ashton","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_18","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_19","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_20","first-page":"916","article-title":"High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers","volume":"60","author":"Walenta","year":"2000","journal-title":"Cancer Res."},{"key":"ref_21","first-page":"1","article-title":"Nuclear lactate dehydrogenase A senses ROS to produce \u03b1-hydroxybutyrate for HPV-induced cervical tumor growth","volume":"9","author":"Liu","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Mishra, D., and Banerjee, D. (2019). Lactate Dehydrogenases as Metabolic Links between Tumor and Stroma in the Tumor Microenvironment. Cancers, 11.","DOI":"10.3390\/cancers11060750"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/nature13490","article-title":"Functional polarization of tumour-associated macrophages by tumour-derived lactic acid","volume":"513","author":"Colegio","year":"2014","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"eaay0555","DOI":"10.1126\/sciimmunol.aay0555","article-title":"VEGF-A drives TOX-dependent T cell exhaustion in anti\u2013PD-1\u2013resistant microsatellite stable colorectal cancers","volume":"4","author":"Kim","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.4049\/jimmunol.177.2.1062","article-title":"Epigenetic Remodeling of the IL-2 and IFN-\u03b3 Loci in Memory CD8 T Cells Is Influenced by CD4 T Cells","volume":"177","author":"Northrop","year":"2006","journal-title":"J. Immunol."},{"key":"ref_26","first-page":"575","article-title":"Metabolic regulation of gene expression by histone lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e50663","DOI":"10.7554\/eLife.50663","article-title":"Lactate-mediated epigenetic reprogramming regulates formation of human pancreatic cancer-associated fibroblasts","volume":"8","author":"Bhagat","year":"2019","journal-title":"eLife"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1023\/A:1022106910017","article-title":"Baseline levels of glucose metabolites, glutamate and glycerol in malignant glioma assessed by stereotactic microdialysis","volume":"61","author":"Roslin","year":"2003","journal-title":"J. Neuro-Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1074\/mcp.M400009-MCP200","article-title":"Proteomic Characterization of the Interstitial Fluid Perfusing the Breast Tumor Microenvironment","volume":"3","author":"Celis","year":"2004","journal-title":"Mol. Cell. Proteom."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s11060-008-9625-2","article-title":"Glucose metabolites, glutamate and glycerol in malignant glioma tumours during radiotherapy","volume":"90","author":"Tabatabaei","year":"2008","journal-title":"J. Neuro-Oncol."},{"key":"ref_31","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_32","first-page":"1","article-title":"Strategies for having a more effective and less toxic CAR T-cell therapy for acute lymphoblastic leukemia","volume":"37","author":"Boroojerdi","year":"2020","journal-title":"Med. Oncol."},{"key":"ref_33","first-page":"166","article-title":"FDA approves fourth CAR-T cell therapy","volume":"20","author":"Mullard","year":"2021","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"270","DOI":"10.3389\/fimmu.2017.00270","article-title":"Impact of Metabolism in on T-Cell Differentiation and Function and Cross Talk with Tumor Microenvironment","volume":"8","author":"Kouidhi","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/s41577-020-0406-2","article-title":"Lactate modulation of immune responses in inflammatory versus tumour microenvironments","volume":"21","author":"Certo","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_36","first-page":"1","article-title":"T-cells produce acidic niches in lymph nodes to suppress their own effector functions","volume":"11","author":"Wu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1097\/MCO.0b013e3281e72ad4","article-title":"Glucose metabolism in lymphoid and inflammatory cells and tissues","volume":"10","author":"Calder","year":"2007","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"eabb8969","DOI":"10.1126\/scitranslmed.abb8969","article-title":"Metabolic reprogramming of donor T cells enhances graft-versus-leukemia effects in mice and humans","volume":"12","author":"Uhl","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/jmri.20902","article-title":"Lactate, choline, and creatine levels measured by vitro1H-MRS as prognostic parameters in patients with non-small-cell lung cancer","volume":"25","author":"Yokota","year":"2007","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"108500","DOI":"10.1016\/j.celrep.2020.108500","article-title":"Lactate Limits T Cell Proliferation via the NAD(H) Redox State","volume":"33","author":"Quinn","year":"2020","journal-title":"Cell Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/ncponc0581","article-title":"The management of tumor lysis syndrome","volume":"3","author":"Rampello","year":"2006","journal-title":"Nat. Clin. Pr. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0167-8140(84)80077-8","article-title":"The relevance of tumour pH to the treatment of malignant disease","volume":"2","author":"Haveman","year":"1984","journal-title":"Radiother. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1084\/jem.20100619","article-title":"VISTA, a novel mouse Ig superfamily ligand that negatively regulates T cell responses","volume":"208","author":"Wang","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1933","DOI":"10.1158\/0008-5472.CAN-13-1506","article-title":"VISTA Regulates the Development of Protective Antitumor Immunity","volume":"74","author":"Chen","year":"2014","journal-title":"Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.it.2020.12.008","article-title":"VISTA: A Mediator of Quiescence and a Promising Target in Cancer Immunotherapy","volume":"42","author":"Yuan","year":"2021","journal-title":"Trends Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/s41586-019-1674-5","article-title":"VISTA is an acidic pH-selective ligand for PSGL","volume":"574","author":"Johnston","year":"2019","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nm.4308","article-title":"VISTA is an inhibitory immune checkpoint that is increased after ipilimumab therapy in patients with prostate cancer","volume":"23","author":"Gao","year":"2017","journal-title":"Nat. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1038\/modpathol.2017.89","article-title":"Negative immune checkpoint regulation by VISTA: A mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients","volume":"30","author":"Kakavand","year":"2017","journal-title":"Mod. Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.imlet.2015.07.003","article-title":"Effects of extracellular pH and hypoxia on the function and development of antigen-specific cytotoxic T lymphocytes","volume":"167","author":"Nakagawa","year":"2015","journal-title":"Immunol. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1007\/s00262-017-1954-6","article-title":"PD-1 and PD-L1 antibodies in cancer: Current status and future directions","volume":"66","author":"Balar","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S0006-2952(98)00330-X","article-title":"Inhibition and uncoupling of oxidative phosphorylation by nonsteroidal anti-inflammatory drugs","volume":"57","author":"Bravo","year":"1999","journal-title":"Biochem. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.celrep.2019.08.068","article-title":"Restricting Glycolysis Preserves T Cell Effector Functions and Augments Checkpoint Therapy","volume":"29","author":"Renner","year":"2019","journal-title":"Cell Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1479-7364-5-1-30","article-title":"Evolutionary divergence and functions of the human interleukin (IL) gene family","volume":"5","author":"Brocker","year":"2010","journal-title":"Hum. Genom."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1146\/annurev-med-073118-011031","article-title":"Engineering IL-2 to Give New Life to T Cell Immunotherapy","volume":"72","author":"Overwijk","year":"2021","journal-title":"Annu. Rev. Med."},{"key":"ref_55","first-page":"350","article-title":"IL-21 and TGF-\u03b2 are required for differentiation of human TH17 cells","volume":"454","author":"Yang","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13125","DOI":"10.18632\/oncotarget.24442","article-title":"IL-21 modulates memory and exhaustion phenotype of T-cells in a fatty acid oxidation-dependent manner","volume":"9","author":"Loschinski","year":"2018","journal-title":"Oncotarget"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6047","DOI":"10.1073\/pnas.1920413117","article-title":"Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+T cell stemness and antitumor immunity","volume":"117","author":"Hermans","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.omtm.2020.07.008","article-title":"Enhancing Chimeric Antigen Receptor T Cell Anti-tumor Function through Advanced Media Design","volume":"18","author":"Ghassemi","year":"2020","journal-title":"Mol. Ther. Methods Clin. Dev."},{"key":"ref_59","first-page":"47","article-title":"Carnosine and anserine concentrations in the quadriceps femoris muscle of healthy humans","volume":"64","author":"Mannion","year":"1992","journal-title":"Graefe\u2019s Arch. Clin. Exp. Ophthalmol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0047-6374(00)00211-6","article-title":"The effects of carnosine on oxidative DNA damage levels and in vitro lifespan in human peripheral blood derived CD4+T cell clones","volume":"121","author":"Hyland","year":"2001","journal-title":"Mech. Ageing Dev."}],"container-title":["Antibodies"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4468\/10\/3\/25\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:25:27Z","timestamp":1760163927000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4468\/10\/3\/25"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":60,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["antib10030025"],"URL":"https:\/\/doi.org\/10.3390\/antib10030025","relation":{},"ISSN":["2073-4468"],"issn-type":[{"value":"2073-4468","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]}}}