Oxygen self-supplying nanoradiosensitizer activates cGAS-STING pathway to enhance radioimmunotherapy of triple negative breast cancer

Radiotherapy (RT)-mediated immune activation is insufficient for effective therapy of triple-negative breast cancer (TNBC) due to the immunosuppressive tumor microenvironment. Herein, we developed an oxygen selfsupplying nanoradiosensitizer to activate immunogenic cell death (ICD) and the cGAS-STING signaling pathway, elevating the anti-tumor immune response and improving radioimmunotherapy for TNBC. The nanoradiosensitizer was fabricated using astragaloside liposome-encapsulated FePt alloy and MnO nanocrystals (ALFM). The ALFM targeted the glucose transporter-1 (GLUT-1) receptor in TNBC and effectively entered tumor cells. Subsequently, the ALFM responded to the weakly acidic tumor microenvironment and degraded, releasing FePt and Mn2+ ions. The released Mn2+ ions not only elevated cellular ROS levels via a Fenton-like reaction but also activated the cGAS-STING signaling pathway, which stimulated the anti-tumor immune response. In addition, the FePt alloy catalyzed a cascade reaction, producing ROS and O2 in tumor cells, alleviating tumor hypoxia, and enhancing the RT effect. Besides, ROS-mediated cell damage induced the ICD effect in TNBC, promoted dendritic cell maturation and the infiltration of cytotoxic T lymphocytes, ultimately eliciting cancer immunotherapy. In vivo experimental results demonstrated that ALFM effectively activated the antitumor immune response and improved the radioimmunotherapy effect for TNBC. Overall, this work presents an effective strategy for enhanced radioimmunotherapy of TNBC.