Abstract
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 Cu(2)O 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(2+)-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.