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

Abstract

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 Ti3C2Tx nanosheets as a protection layer to maximize the therapeutic effects of tumor-specific cuproptosis. A Z-scheme heterojunction termed Cu2O/Ti3C2Tx is facilely constructed by coating Ti3C2Tx nanosheets on the surface of Cu2O nanocubes. The fabrication of heterojunctions not only improves the sonodynamic and chemodynamic activities of Cu2O nanocubes owing to the manipulation of electron-hole transfer process, but also avoids the degradation of Cu2O 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 Cu2+-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.