Carbon dot sensitized Cu3P sonozymes for cuproptosis-enhanced and heterojunction-amplified sono-immunotherapy through activating cGAS-STING pathway

It is believed that the poor response of patients and the immunosuppressive tumor microenvironment (TME) severely limit the clinical application of lung cancer immunotherapy. Herein, the cascade amplification of anticancer immune response is realized by the integration of heterojunction-amplified ROS production and cuproptosis-enhanced cGAS-STING activation. Cu₂O-derived multifunctional Cu₃P nanocubes can serve as a high-efficiency cuproptosis inducer, sonosensitizer, and nanozyme for cuproptosis-enhanced sonodynamic and chemodynamic therapy (SDT and CDT). To further augment the sonozyme activities of Cu₃P nanocubes, we utilize NIR phosphorescent carbon dots (CDs) as the auxiliary sonosensitizers to sensitize Cu₃P nanocubes for the fabrication of CD/Cu₃P heterojunction nanoplatforms. CD/Cu₃P-triggered durable and potent immune responses are first induced by the ROS-triggered ICD effect, which co-amplified by the heterojunction construction and GSH depletion. The immunosuppressive TME is further reversed by the CD/Cu₃P-mediated cuproptosis effect, which then activates the cGAS-STING pathway. Significant antitumor effectiveness have been found to eliminate primary tumors and inhibit the growth of distant tumors through CD/Cu₃P-induced synergistic SDT, CDT, cuproptosis, and cGAS-STING activation. Overall, this study introduces a new approach to explore Cu-based sonozymes for heterojunction-augmented and cuproptosis-enhanced sono-immunotherapy through activating the cGAS-STING pathway.