{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:38:01Z","timestamp":1792517881686,"version":"4.5.0"},"reference-count":113,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004836","name":"Danmarks Frie Forskningsfond","doi-asserted-by":"publisher","award":["0135\u201000139B"],"award-info":[{"award-number":["0135\u201000139B"]}],"id":[{"id":"10.13039\/501100004836","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008363","name":"Kr\u00e6ftens Bek\u00e6mpelse","doi-asserted-by":"publisher","award":["R204\u2010A12359"],"award-info":[{"award-number":["R204\u2010A12359"]}],"id":[{"id":"10.13039\/100008363","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008363","name":"Kr\u00e6ftens Bek\u00e6mpelse","doi-asserted-by":"publisher","award":["R269\u2010A15823"],"award-info":[{"award-number":["R269\u2010A15823"]}],"id":[{"id":"10.13039\/100008363","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF19OC0058262"],"award-info":[{"award-number":["NNF19OC0058262"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF21OC0069598"],"award-info":[{"award-number":["NNF21OC0069598"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","award":["NNF24OC0088960"],"award-info":[{"award-number":["NNF24OC0088960"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002808","name":"Carlsbergfondet","doi-asserted-by":"publisher","award":["CF20\u20100491"],"award-info":[{"award-number":["CF20\u20100491"]}],"id":[{"id":"10.13039\/501100002808","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002808","name":"Carlsbergfondet","doi-asserted-by":"publisher","award":["CF23\u20101744"],"award-info":[{"award-number":["CF23\u20101744"]}],"id":[{"id":"10.13039\/501100002808","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Solid tumors are characterized by profound metabolic and vascular abnormalities that generate a hostile tumor microenvironment (TME) marked by extracellular acidosis, hypoxia, and nutrient deprivation. While the consequences of these conditions for cancer cell behavior have been extensively studied, their impact on anti\u2010tumor immune responses\u2014particularly T cell function\u2014has only recently gained attention. In this review, we summarize and critically discuss current knowledge on how acidic TME conditions affect the cytotoxic CD8+ T cells which are essential for anti\u2010tumor immunity, and the protumorigenic, regulatory T cells (Tregs). An emerging body of literature shows that TME acidosis restricts cytotoxic CD8+ T cell motility and tumor penetration, suppresses cytokine production and secretion despite preserved transcription, impairs proliferation, and reduces cytotoxic killing capacity. These effects are closely linked to acid\u2010induced metabolic reprogramming, including inhibition of glycolysis, altered mTOR and MYC signaling, and a shift toward fatty acid\u2010dependent oxidative metabolism. In contrast, Tregs, which are metabolically adapted to rely on oxidative phosphorylation and lactate utilization, are comparatively resilient to acidic stress, and acidosis can enhance their suppressive capacity, thereby further skewing the immune balance toward tolerance. We highlight emerging evidence that tumor acidosis modulates immune checkpoint pathways, including pH\u2010sensitive signaling through VISTA and regulation of PD\u2010L1 expression, with important implications for immunotherapy sensitivity. We posit that limiting tumor acidosis may enable restoration of anti\u2010tumor T cell function and improve therapeutic response to immune checkpoint blockade and adoptive T cell therapies.<\/jats:p>","DOI":"10.1111\/apha.70260","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T07:06:49Z","timestamp":1779433609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["T Cell Dysfunction in the Acidic Tumor Microenvironment"],"prefix":"10.1111","volume":"242","author":[{"given":"F. B.","family":"Christiansen","sequence":"first","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. S.","family":"Novella","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. V.","family":"Lindemann","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. F. H.","family":"Cordes","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. F.","family":"Pedersen","sequence":"additional","affiliation":[{"name":"Section for Cell Biology and Physiology, Department of Biology University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"e_1_2_16_2_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physiol-021119-034627"},{"key":"e_1_2_16_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-023-00628-9"},{"key":"e_1_2_16_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.77"},{"key":"e_1_2_16_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.10.038"},{"key":"e_1_2_16_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0501"},{"key":"e_1_2_16_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-022-00520-5"},{"key":"e_1_2_16_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00574-3"},{"key":"e_1_2_16_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00521-2"},{"key":"e_1_2_16_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2018.07.009"},{"key":"e_1_2_16_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-1743"},{"key":"e_1_2_16_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00262-022-03228-y"},{"key":"e_1_2_16_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.09.005"},{"key":"e_1_2_16_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/35105024"},{"key":"e_1_2_16_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2024.01.013"},{"key":"e_1_2_16_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.2RI0717-278R"},{"key":"e_1_2_16_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20221839"},{"key":"e_1_2_16_18_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.1.241"},{"key":"e_1_2_16_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3405"},{"key":"e_1_2_16_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.04.020"},{"key":"e_1_2_16_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.12.002"},{"key":"e_1_2_16_22_1","article-title":"CD8+ Regulatory T Cells","volume":"5","author":"Vuttaradhi V. K.","year":"2025","journal-title":"Annual Review of Immunology"},{"key":"e_1_2_16_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2020.06.003"},{"key":"e_1_2_16_24_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-012017-043208"},{"key":"e_1_2_16_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.80"},{"key":"e_1_2_16_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.011"},{"key":"e_1_2_16_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0266-5"},{"key":"e_1_2_16_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-025-02327-3"},{"key":"e_1_2_16_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9"},{"key":"e_1_2_16_30_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.290.5492.816"},{"key":"e_1_2_16_31_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-16-1761"},{"key":"e_1_2_16_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0313-5"},{"key":"e_1_2_16_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06026-3"},{"key":"e_1_2_16_34_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aay0524"},{"key":"e_1_2_16_35_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1822001116"},{"key":"e_1_2_16_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2020.12.008"},{"key":"e_1_2_16_37_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0710441105"},{"key":"e_1_2_16_38_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1506"},{"key":"e_1_2_16_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2011.07.003"},{"key":"e_1_2_16_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-024-01089-x"},{"key":"e_1_2_16_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1093"},{"key":"e_1_2_16_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2020.07.022"},{"key":"e_1_2_16_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-024-02156-y"},{"key":"e_1_2_16_44_1","article-title":"Regulators of CD8+ T Cell Exhaustion","volume":"25","author":"Sun Q.","year":"2025","journal-title":"Nature Reviews Immunology"},{"key":"e_1_2_16_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-024-01188-5"},{"key":"e_1_2_16_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06568-6"},{"key":"e_1_2_16_47_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-34242-4"},{"key":"e_1_2_16_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17756-7"},{"issue":"23","key":"e_1_2_16_49_1","first-page":"6449","article-title":"Blood Flow, Oxygen and Nutrient Supply, and Metabolic Microenvironment of Human Tumors: A Review","volume":"49","author":"Vaupel P.","year":"1989","journal-title":"Cancer Research"},{"key":"e_1_2_16_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1991.326"},{"key":"e_1_2_16_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113796"},{"key":"e_1_2_16_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-022-00470-2"},{"key":"e_1_2_16_53_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-023-01644-1"},{"key":"e_1_2_16_54_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1272"},{"key":"e_1_2_16_55_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-07-035972"},{"key":"e_1_2_16_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.08.011"},{"key":"e_1_2_16_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-022-00730-6"},{"key":"e_1_2_16_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-025-01347-1"},{"key":"e_1_2_16_59_1","doi-asserted-by":"publisher","DOI":"10.1038\/287558a0"},{"key":"e_1_2_16_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4827(86)90029-7"},{"key":"e_1_2_16_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13068"},{"key":"e_1_2_16_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-024-00235-w"},{"key":"e_1_2_16_63_1","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200109)31:9<2829::AID-IMMU2829>3.0.CO;2-U"},{"key":"e_1_2_16_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.01.040"},{"key":"e_1_2_16_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.05.016"},{"key":"e_1_2_16_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2024.11.010"},{"key":"e_1_2_16_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1119744109"},{"key":"e_1_2_16_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2035"},{"key":"e_1_2_16_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2024.08.004"},{"key":"e_1_2_16_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.imlet.2015.07.003"},{"key":"e_1_2_16_71_1","first-page":"138","article-title":"Colorectal Cancer Extracellular Acidosis Decreases Immune Cell Killing and Is Partially Ameliorated by pH\u2010Modulating Agents That Modify Tumor Cell Cytokine Profiles","volume":"12","author":"Huntington K. E.","year":"2022","journal-title":"American Journal of Cancer Research"},{"key":"e_1_2_16_72_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0203-y"},{"key":"e_1_2_16_73_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05937-3"},{"key":"e_1_2_16_74_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.7.4476"},{"key":"e_1_2_16_75_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abb8969"},{"key":"e_1_2_16_76_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34404"},{"key":"e_1_2_16_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.05.009"},{"key":"e_1_2_16_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.06.005"},{"key":"e_1_2_16_79_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.202250258"},{"key":"e_1_2_16_80_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-025-00832-9"},{"key":"e_1_2_16_81_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-025-03458-1"},{"key":"e_1_2_16_82_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03045-2"},{"key":"e_1_2_16_83_1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3577"},{"key":"e_1_2_16_84_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-22-1301"},{"key":"e_1_2_16_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2022.01.001"},{"key":"e_1_2_16_86_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2025.111956"},{"key":"e_1_2_16_87_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.114409"},{"key":"e_1_2_16_88_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-022-09956-9"},{"key":"e_1_2_16_89_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33786"},{"key":"e_1_2_16_90_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-023-01900-0"},{"key":"e_1_2_16_91_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-24-4774"},{"key":"e_1_2_16_92_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.70415"},{"key":"e_1_2_16_93_1","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15637"},{"key":"e_1_2_16_94_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0685"},{"key":"e_1_2_16_95_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.768579"},{"key":"e_1_2_16_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2024.101930"},{"key":"e_1_2_16_97_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.03.006"},{"key":"e_1_2_16_98_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aaf0685"},{"key":"e_1_2_16_99_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1706169"},{"key":"e_1_2_16_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.07.013"},{"key":"e_1_2_16_101_1","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12141"},{"key":"e_1_2_16_102_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0218-4"},{"key":"e_1_2_16_103_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1674-5"},{"key":"e_1_2_16_104_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1811067116"},{"key":"e_1_2_16_105_1","doi-asserted-by":"publisher","DOI":"10.1002\/bies.201600253"},{"key":"e_1_2_16_106_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-024-02918-z"},{"key":"e_1_2_16_107_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12020461"},{"key":"e_1_2_16_108_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2019.11.004"},{"key":"e_1_2_16_109_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.263688"},{"key":"e_1_2_16_110_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ade5686"},{"key":"e_1_2_16_111_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-025-02065-y"},{"key":"e_1_2_16_112_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9752"},{"key":"e_1_2_16_113_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2018.00101"},{"key":"e_1_2_16_114_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.abf9419"}],"container-title":["Acta Physiologica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.70260","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/apha.70260","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/apha.70260","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T05:05:25Z","timestamp":1779512725000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/apha.70260"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,22]]},"references-count":113,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1111\/apha.70260"],"URL":"https:\/\/doi.org\/10.1111\/apha.70260","archive":["Portico"],"relation":{},"ISSN":["1748-1708","1748-1716"],"issn-type":[{"value":"1748-1708","type":"print"},{"value":"1748-1716","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,22]]},"assertion":[{"value":"2026-02-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-22","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70260"}}