Tumor microenvironment activated MXene-protected Cu2O heterojunctions induce tumor-specific cuproptosis for enhanced sono-immunotherapy

• MXene is utilized as a protection layer to control the degradation behaviors of Cu 2 O. • MXene is coated on Cu 2 O nanocubes to form a Z-scheme heterojunction . • The cascaded amplification of ROS production and tumor-specific cuproptosis are achieved. • Immunosuppressive TME is reversed by enhanced ROS generation and cuproptosis effect. • Cu 2 O/Ti 3 C 2 T x realizes tumor-specific cuproptosis-enhanced SDT, CDT, and immunotherapy . The utilization of a copper ionophore to induce programmed cell death, known as cuproptosis, shows potential in augmenting the efficacy of traditional anticancer treatments and eliciting robust adaptive immune responses. Nevertheless, the non-tumor-specific release of Cu ions may initiate cuproptosis and cause irreversible damage to normal tissues. Herein, this work reports for the first time the regulation of degradation behaviors of Cu-based nanomaterials using Ti 3 C 2 T x nanosheets as a protection layer to maximize the therapeutic effects of tumor-specific cuproptosis. A Z-scheme heterojunction termed Cu 2 O/Ti 3 C 2 T x is facilely constructed by coating Ti 3 C 2 T x nanosheets on the surface of Cu 2 O nanocubes. The fabrication of heterojunctions not only improves the sonodynamic and chemodynamic activities of Cu 2 O nanocubes owing to the manipulation of electron-hole transfer process, but also avoids the degradation of Cu 2 O nanocubes under normal physiological conditions. The tumor-specific released Cu ions not only realized the cascade amplification of ROS generation through Cu + -mediated Fenton-like reaction and Cu 2+ -facilitated GSH depletion, but also triggered cuproptosis through Cu + -induced DLAT oligomerization and mitochondrial dysfunction. More importantly, the immunosuppressive TME could be reversed by the greatly enhanced ROS levels and high-efficiency cuproptosis, ultimately inducing immunogenic cell death that promotes robust systemic immune responses for the eradication of primary tumors and suppression of distant tumors. This work provides a promising perspective for potential cancer treatment based on tumor-specific cuproptosis by controlling the degradation behaviors of Cu-based nanomaterials.