{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:05:45Z","timestamp":1784786745658,"version":"3.55.0"},"reference-count":95,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Immune checkpoint blockade has transformed cancer therapy, yet many tumors remain intrinsically resistant or acquire resistance after initial response. Increasing evidence indicates that this failure is not determined solely by PD-1, PD-L1, CTLA-4, or T-cell exhaustion, but also by metabolically suppressive states within the tumor microenvironment. Tumor-derived metabolites can function as metabolic immune checkpoints by limiting effector immune activity, promoting regulatory or myeloid suppressive compartments, and weakening immunotherapy efficacy. This mini review summarizes recent experimental evidence showing how lactate, adenosine, tryptophan-derived metabolites, and nucleotide-derived metabolites shape immune escape and resistance to immune checkpoint blockade. Lactate links tumor glycolysis to Treg recruitment, impaired T-cell function, and lactylation-associated therapeutic resistance. The CD73-adenosine axis suppresses CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells and natural killer cells while reinforcing regulatory and myeloid immune programs. Tryptophan-derived metabolites extend beyond the classical IDO1\u2013kynurenine\u2013AhR pathway to involve non-classical checkpoints such as Siglec-15 and broader kynurenine\/indole\/serotonin networks. Emerging evidence further identifies nucleotide-derived UDP signaling as a driver of macrophage-mediated immunosuppression. Finally, we discuss how targeting metabolic checkpoints in combination with immune checkpoint blockade may improve therapeutic responses. Defining the spatial and cellular contexts of metabolite-mediated immune suppression may enable more precise strategies to overcome immunotherapy resistance.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1894658","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:38:23Z","timestamp":1784785103000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"Renjie","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Clinical Laboratory, Xinghua People\u2019s Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongdong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Fifth People\u2019s Hospital of Ganzhou","place":["Ganzhou, Jiangxi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yilu","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Third People\u2019s Hospital of Longgang District Shenzhen","place":["Shenzhen, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lancheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xinghua People's Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Xinghua People's Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Li","sequence":"additional","affiliation":[{"name":"Xinghua People's Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuxia","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Xinghua People\u2019s Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Xinghua People\u2019s Hospital Affiliated to Yangzhou University","place":["Xinghua, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.115339","article-title":"Aptamers as immune checkpoint inhibitors in cancer immunotherapy: targeting CTLA-4\/B7 and PD-1\/PD-L1 pathways","volume":"164","author":"Anantha 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