X-ray-Responsive Cascade System for Radioimmunotherapy: Tumor Microenvironment Remodeling and Controllable NO Release

Abstract Radioimmunotherapy holds great promise for the treatment of solid tumors. However, radioresistance and immunosuppression mediated by a tumor microenvironment (TME) severely restrict radiation-induced immunogenic cell death (ICD), facilitate tumor relapse and metastatic dissemination, and ultimately compromise the therapeutic efficacy of radioimmunotherapy. Herein, we report a multifunctional cascade AuPt/SnO2–x@MOF@Arg nanoplatform to remodel TME and boost radioimmunotherapy synergistically. This system integrates X-ray-responsive peroxidase (POD), catalase(CAT), glucose oxidase (GOD), and glutathione oxidase (GSHOx) activities to achieve cascade-amplified reactive oxygen species (ROS) and controllable NO release. The structure, X-ray-induced cascade multienzyme functions, ICD activation by efficient ROS, and controllable release of high-concentration NO have been proved fully in the APSMA NPs. In vitro experiments demonstrate that a high apoptosis rate of 94.8% against 4T1 cells can be achieved by a synergistic cascade therapeutic system through inducing cell apoptosis via efficient production of ROS and arresting the cell cycle at the radiation-sensitive G2/M phase. In an in situ breast cancer model, the combined therapy effectively reduces tumor volume, and the final tumor volume is 4% of that in the X-ray group. Studies on the mechanisms underlying the immunosuppressive microenvironment reveal that NO remodels the TME by downregulating transforming growth factor beta (TGF-β), thereby inhibiting epithelial-mesenchymal transition (EMT)-associated proteins to suppress tumor metastasis and abnormal angiogenesis. Furthermore, TGF-β suppression enhances the infiltration of CD8+ T cells and reduces the proportion of FOXP3+ regulatory T cells, reversing immune suppression. This multifunctional nanozyme platform provides a robust strategy for efficient radioimmunotherapy.