A Self‐Reinforcing Metabolic Nanojammer for Activating Cascade‐Augmented Cuproptosis‐Driven Immunotherapy

Abstract Cuproptosis, an emerging modality of copper‐induced programmed cell death, holds great promise for cancer therapy. However, its therapeutic efficacy is seriously limited by the tumor cells’ intrinsic metabolic plasticity and copper homeostatic mechanisms. Herein, a self‐reinforcing metabolic nanojammer (HMCZH) based on copper‐doped zeolitic imidazolate framework nanoparticles co‐delivering oxygenated hemoglobin (Oxy‐Hb) and mitochondria‐targeted dichloroacetic acid (Mito‐DCA) has been engineered. HMCZH disrupts intracellular copper homeostasis by depleting glutathione, which acts as a copper chelator, and inhibiting Cu‐ATPase‐mediated copper efflux via hydroxyl radicals generated through Fenton‐like reactions. Simultaneously, delivered O 2 and Mito‐DCA reprogramming tumor metabolism from glycolysis to oxidative phosphorylation (OXPHOS), synergizing with copper overload to amplify cuproptosis. This glycolysis‐to‐OXPHOS metabolic shift enhances tumor immunogenicity and alleviates the immunosuppressive microenvironment, thereby activating a robust systemic immune response against tumor development and metastasis. Overall, this work introduces a rationally designed nanoplatform that couples metabolic switch with copper homeostasis disruption to potentiate cuproptosis‐driven immunotherapy.