Graphene Quantum Dot Sensitized Heterojunctions Induce Tumor-Specific Cuproptosis to Boost Sonodynamic and Chemodynamic Enhanced Cancer Immunotherapy.

Cuproptosis that utilizes copper ionophore to induce programmed cell death holds promise for enhancing the effectiveness of conventional anticancer therapies and triggering efficient adaptive immune responses. However, the non-tumor-specific release of Cu ions can induce cuproptosis and cause irreversible damage to normal tissues. To maximize the therapeutic effects of tumor-specific cuproptosis, this work reports for the first time the regulation of degradation behaviors of Cu-based nanomaterials using graphene quantum dots (GQDs) as a protection layer. The deposition of GQDs not only avoids the degradation of CuO nanocubes under normal physiological conditions, but also sensitizes their sonodynamic activity due to the formation of Z-scheme heterojunctions. The tumor-specific released Cu ions achieve the cascade amplification of reactive oxygen species (ROS) generation through Cu-mediated Fenton-like reaction and Cu-facilitated GSH depletion. More importantly, the immunosuppressive tumor microenvironment (TME) can 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 novel paradigm for the integration of SDT, CDT, cuproptosis, and immunotherapy in a controlled manner to achieve tumor-specific antitumor therapy by controlling the degradation behaviors of Cu-based nanomaterials.