A pH-Responsive Nanoplatform Inducing Synergistic Cuproptosis and Pyroptosis Reprograms the Immunosuppressive Tumor Microenvironment for Enhanced Immunotherapy

In this study, a pH-responsive Cu-doped zeolitic imidazolate framework-8 nanoplatform was coloaded with paclitaxel and doxorubicin for synergistic tumor therapy. Hyaluronic acid modification on the outer surface of the nanomaterials enhances tumor targeting via CD44 receptor-mediated endocytosis. ZIF-8, derived from metal–organic frameworks, is an excellent nanocapsulator capable of specifically responding to the acidic tumor microenvironment. Upon reaching the tumor site, it rapidly degrades, releasing copper ions and chemotherapeutic drugs to exert antitumor effects. Copper ions consume endogenous hydrogen peroxide and glutathione through Fenton-like reactions, thereby generating cytotoxic reactive oxygen species, enhancing chemodynamic therapy efficiency, and inducing cuproptosis. The released PTX and DOX not only exert chemotherapeutic effects but also induce pyroptosis by activating the classical pathway mediated by caspase-3 and Gasdermin E. Due to excessive activation of the Wnt/β-catenin signaling pathway, PTX faces drug resistance in the treatment of triple-negative breast cancer, whereas DOX can inhibit this pathway by promoting β-catenin degradation. These therapies act synergistically to trigger immunogenic cell death, release damage-associated molecular patterns, promote dendritic cell maturation, activate T cells, and effectively reshape the immunosuppressive tumor microenvironment. This multimodal nanoplatform demonstrates remarkable potential as an antitumor treatment.