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Chronic stresses within TME compromise canonical cap\u2010dependent translation (CDT), which compromises effector T cell function but not Treg persistence. Death\u2010associated protein 5 (DAP5\/eIF4G2), a non\u2010classical translational scaffold, has been reported to support human Treg differentiation in vitro, but its functions in thymic Treg development, peripheral Treg homeostasis, and tumor\u2010infiltrating Treg (ti\u2010Treg) fitness remain unclear. Here, it is shown that DAP5 expression positively correlates with ti\u2010Treg frequencies in both colorectal cancer patients and murine subcutaneous tumors. Mice with homozygous Dap5 deletion in Tregs has intact thymic and peripheral Treg development but spontaneously developed typical scurfy symptoms. Haploinsufficiency of Dap5 in Tregs preserves peripheral immune homeostasis while suppressing tumor growth, with enhanced CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration and effector function. Mechanistically, Dap5 mediates alternate mode of translation of transcripts encoding CD25 and MCL\u20101 in Tregs, thereby sustaining Treg lineage stability and survival in the stressful TME. Overall, Tregs rely on DAP5\u2010driven alternate translation to maintain peripheral homeostasis and acquired fitness within the TME. Selective disruption of this pathway impairs ti\u2010Tregs while sparing systemic tolerance, offering a potential therapeutic strategy to enhance anti\u2010tumor immunity.\n                  <\/jats:p>","DOI":"10.1002\/advs.202520625","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T05:52:12Z","timestamp":1766987532000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting DAP5 Disrupts Alternate Mode of Translational Initiation in Tregs and Potentiates Antitumor Immunity"],"prefix":"10.1002","volume":"13","author":[{"given":"Xiaojiang","family":"Lai","sequence":"first","affiliation":[{"name":"Precision Research Center for Refractory Diseases, State Key Laboratory of Innovative Immunotherapy Institute for Clinical Research Shanghai Key Laboratory of Pancreatic Diseases Department of Gastrointestinal Surgery Department of Gastroenterology Department of Nursing Department of 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