Biomimetic Copper Nanozyme Reprograms Cold Tumor via Cuproptosis-Pyroptosis Crosstalk for Potent Renal Carcinoma Immunotherapy.

Immune checkpoint blockade (ICB) therapy is an emerging strategy for renal cell carcinoma (RCC). However, its clinical efficacy remains constrained by its inherently poor immunogenicity and insufficient cytotoxic T lymphocyte (CTL) infiltration. Herein, we engineer a biomimetic copper nanozyme (Cu2O-OMV) by integrating Cu2O nanoparticles with bacterial outer-membrane vesicles (OMVs) to activate the antitumor immune response and synergize with ICB therapy. The Cu2O-OMV nanozyme exhibits peroxidase (POD)-like catalytic activity and releases Cu+ to exert Fenton-like activity, generating cytotoxic hydroxyl radicals (·OH) for tumor inhibition. Furthermore, Cu+ accumulation promotes the occurrence of cuproptosis, leading to the mitochondrial aggregation of lipoylated dihydrolipoamide S-acetyltransferase and depletion of ferredoxin 1. Notably, Cu2O-OMV concurrently activates pyroptosis via the noncanonical inflammasome pathway through its intrinsic lipopolysaccharide cargo, directly inhibiting tumor growth and inducing inflammatory cytokine release. The coordinated induction of cuproptosis and pyroptosis synergistically amplifies immunogenic cell death to enhance tumor immunogenicity, thereby promoting dendritic cell maturation and CTL infiltration. After combining with αPD-L1, it effectively destroys tumor cells to activate the antitumor immune response, thereby inhibiting tumor metastasis. Our study demonstrates a biomimetic nanozyme-driven strategy that harnesses dual cuproptosis-pyroptosis pathways to enhance the tumor immunogenicity and amplify the ICB efficacy, offering a transformative approach for RCC immunotherapy.