Bimetallic Cu/Fe-MOF-based heterojunction sonozymes for triple amplification of sono-immunotherapy through activating tumor-specific cuproptosis and cGAS-STING pathway

Background: Initiating ROS-induced ICD and activating innate immune pathways are promising strategies for reprogramming immunosuppressive TME and eliciting persistent antitumor immune responses. Methods: enable FCMM as a high-efficiency sonozyme, achieving enhanced ROS production through heterojunction-mediated sonodynamic activity amplification and Fe/Cu/Mn-ion-triggered multienzyme-mimic activities including Fenton/Fenton-like reaction, GSH depletion, and hypoxia alleviation. Results: The reversal of the immunosuppressive tumor microenvironment occurs through the ROS-triggered ICD and the enhancement of DC cell maturation. More importantly, the activation of the Mn ions-mediated cGAS-STING pathway further boosts the maturation of DCs. In addition, the released Cu ions can induce cuproptosis, achieving triple amplification of antitumor immune response. Conclusion: The combination therapy of CDT, SDT, cuproptosis, and cGAS-STING activation via FCMM, achieved complete elimination of primary tumor and significant controlled the growth of distant tumor. This work combines sonocatalytic nanomedicine with immune modulation strategy through integrating ROS amplification, cGAS-STING activation, and cuproptosis effect into a single nanoplatform, providing new insights for the clinical application of sono-immunotherapy.