{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T11:07:36Z","timestamp":1789988856958,"version":"4.0.1"},"reference-count":118,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"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>Immunotherapy has markedly improved outcomes across multiple cancer types; however, colorectal cancer (CRC) remains largely refractory, with meaningful responses mostly restricted to tumors harboring deficient mismatch repair and high microsatellite instability (dMMR\/MSI-H), which represent only a small fraction of CRC cases. Emerging evidence suggests that mitochondrial dysfunction may be viewed as a metabolic checkpoint, representing a conceptual framework through which mitochondrial-dependent processes regulate antitumor immunity and immunotherapy response in CRC. In tumor cells, mitochondrial reprogramming enhances reliance on oxidative phosphorylation, promotes hypoxia, and drives metabolite accumulation, collectively shaping an immunosuppressive tumor microenvironment. In parallel, tumor-infiltrating T-cells exhibit mitochondrial dysfunction characterized by impaired biogenesis, reduced respiratory capacity and features of exhaustion, thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). In this review, we summarize current insights into the role of mitochondrial pathways in regulating tumor immune escape and T-cell dysfunction in CRC. We further discuss emerging therapeutic strategies aimed at targeting metabolic vulnerabilities to overcome resistance and potentially enhance responses to immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1908222","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:57:55Z","timestamp":1789988275000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Lorenzo","family":"Tomassini","sequence":"first","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor Vergata\u201d","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Colella","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine, University of Rome \u201cTor 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