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Although glycolysis inhibition enhances T cell\u2010mediated immune responses, the integrated platforms combining glycolysis inhibition with immunotherapy remain underdeveloped. To address this gap, a glucose metabolism\u2010targeted poly(amino acid) nanoformulation of oxaliplatin(IV)\u2010aspirin prodrug (NP\/OXA\u2010ASP<jats:sub>2<\/jats:sub>) is developed to improve chemo\u2010immunotherapy by suppressing tumor glycolysis. This poly(amino acid) nanoparticle exhibits selective release, discharging 90.0% of OXA\u2010ASP<jats:sub>2<\/jats:sub> under reductive conditions within 36 h. Furthermore, over 80% of the prodrug converts to OXA and ASP within 12 h, promoting mitochondrial damage and glycolysis inhibition, which amplifies immunogenic cell death induced by OXA. In addition, suppressing glycolytic flux reduces lactate leakage, mitigating the immunosuppressive TMEs. Together, these mechanisms contribute to stronger chemo\u2010immunotherapy efficacy. Compared to the OXA plus ASP formulation, NP\/OXA\u2010ASP<jats:sub>2<\/jats:sub> demonstrates superior performances, reducing lactate levels at the tumor site by 25.4%, increasing the proportion of cytotoxic T lymphocytes by 1.53 times, decreasing the proportion of regulatory T cells by 2.20 times, and improving 1.39\u2010fold of the tumor inhibition rate. These findings underscore that NP\/OXA\u2010ASP<jats:sub>2<\/jats:sub> is a promising platform for integrating tumor metabolic regulation with immunomodulation and holds significant potential for advancing clinical chemo\u2010immunotherapy.<\/jats:p>","DOI":"10.1002\/adma.202419033","type":"journal-article","created":{"date-parts":[[2025,2,14]],"date-time":"2025-02-14T06:03:51Z","timestamp":1739513031000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Glucose Metabolism\u2010Targeted Poly(amino acid) Nanoformulation of Oxaliplatin(IV)\u2010Aspirin Prodrug for Enhanced Chemo\u2010Immunotherapy"],"prefix":"10.1002","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1947-9109","authenticated-orcid":false,"given":"Jiazhen","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences  5625 Renmin Street Changchun 130022 P. 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