Glucose Metabolism‐Targeted Poly(amino acid) Nanoformulation of Oxaliplatin(IV)‐Aspirin Prodrug for Enhanced Chemo‐Immunotherapy

Abstract Inappropriate glucose metabolism in cancer cells is associated with immunosuppressive tumor microenvironments (TMEs). Although glycolysis inhibition enhances T cell‐mediated immune responses, the integrated platforms combining glycolysis inhibition with immunotherapy remain underdeveloped. To address this gap, a glucose metabolism‐targeted poly(amino acid) nanoformulation of oxaliplatin(IV)‐aspirin prodrug (NP/OXA‐ASP 2 ) is developed to improve chemo‐immunotherapy by suppressing tumor glycolysis. This poly(amino acid) nanoparticle exhibits selective release, discharging 90.0% of OXA‐ASP 2 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‐immunotherapy efficacy. Compared to the OXA plus ASP formulation, NP/OXA‐ASP 2 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‐fold of the tumor inhibition rate. These findings underscore that NP/OXA‐ASP 2 is a promising platform for integrating tumor metabolic regulation with immunomodulation and holds significant potential for advancing clinical chemo‐immunotherapy.