{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T06:03:33Z","timestamp":1784527413597,"version":"3.55.0"},"reference-count":176,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"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                    The fat mass and obesity-associated protein (FTO), an RNA demethylase acting on both internal m\n                    <jats:sup>6<\/jats:sup>\n                    ;A and cap-proximal m\n                    <jats:sup>6<\/jats:sup>\n                    ;Am, functions in cancer as a context-dependent epitranscriptomic regulator whose net effect cannot be reduced to an oncogene\u2013tumor-suppressor dichotomy. Its biological output is shaped by tumor lineage, subcellular localization, upstream signaling, and competing m\n                    <jats:sup>6<\/jats:sup>\n                    ;A reader activities, predominantly YTHDF2-mediated decay and IGF2BP-mediated stabilization, although both reader families display additional non-canonical functions and are themselves modulated by post-translational modifications. Building on the now well-established context-dependence of FTO biology, which we do not claim as a novel observation, this review synthesizes current evidence on FTO\u2019s roles at the intersection of tumor immune contexture, immune checkpoint regulation, metabolic reprogramming, and therapeutic resistance. We examine how FTO may contribute to immune exclusion through metabolic competition, exosomal signaling, and stromal reprogramming; modulate PD-L1 expression through direct and indirect mechanisms; and influence response to chemotherapy, targeted therapy, radiotherapy, and CNS-directed treatment. Emerging FTO inhibitors, FTO-degraders, and combination strategies with immune checkpoint blockade, ferroptosis inducers, or glycolytic inhibitors are evaluated against their underlying preclinical evidence base. The contribution of this review lies less in proposing a new framework than in three forms of integration typically addressed in isolation: explicit calibration of mechanistic claims to evidence tier, systematic separation of tumor-intrinsic from immune-cell-intrinsic FTO functions across lymphoid and myeloid compartments, and translation of reader-network biology into biomarker-stratified trial design. Technical limitations of epitranscriptomic methods are addressed as constraints on inference. To our knowledge, no FTO-targeted strategy has yet entered Phase I oncology evaluation; current combination rationales therefore remain preclinically supported rather than clinically established.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1861781","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T05:34:23Z","timestamp":1784525663000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Reader-dependent functional duality of FTO: a context-switching node at the intersection of immune evasion and therapeutic resistance"],"prefix":"10.3389","volume":"17","author":[{"given":"WenJie","family":"Tian","sequence":"first","affiliation":[{"name":"Department of Urology, the Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Biliary Surgery, Cancer Hospital of Dalian University of Technology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital& Institute","place":["Shenyang, Liaonin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhan","sequence":"additional","affiliation":[{"name":"Department of Urology, the Second Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1186\/s43556-025-00352-w","article-title":"Drug resistance in cancer: molecular mechanisms 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