HOF-based catalytic platform combining sonodynamic therapy and bioorthogonal activation of immunosuppression reversal for cancer therapy

Combination cancer immunotherapy based on ultrasound (US) and immunotherapy shows potent anti-cancer efficacy. However, most sonosensitizers produce ROS with low efficiency under US. Chemotherapy-induced immunogenic cell death (ICD) is also plagued by toxic side effects, suboptimal efficacy, and immune escape. Herein, the sonosensitizer iron porphyrin (FeTCPPCl) self-assembled into a hydrogen-bonded organic framework (HOF-1) is developed as a cancer therapy platform with the functions of precise activation and spatiotemporal controlled release of the prodrug to induce ICD efficiently and safely. Specifically, pro-DOX can be bioorthogonally activated in situ by HOF-1 to synergize sonodynamic immunotherapy. This strategy, which combines sonodynamic therapy with in situ prodrug activation, minimizes drug side effects and maximizes therapeutic effects. Additionally, the system can catalytically activate pro-metformin (pro-MET), reduce PD-L1 expression, and reverse tumor immunosuppression. Remarkably, it is the first time that sonosensitizers have been self-assembled into an effective catalytic platform to generate in situ bioorthogonally activated prodrug-targeted formulations, providing a paradigm for achieving safe and powerful immunotherapy. This breakthrough technology has broad application prospects in the field of immunotherapy and may significantly improve cancer and other disease treatments.