Radiotherapy-derived engineered stem cell exosomes improve anti-glioma immunotherapy by promoting the formation of tertiary lymphoid structure and improve the release of type I interferon.

The absence of signaling pathways related to intrinsic immune activation in tumor cells and the immunosuppressive microenvironment limit lymphocyte infiltration, constitutes an "immune-desert" tumor displaying insensitivity to various immunotherapies. This study investigates strategies to activate intrinsic immune pathways in glioma cells, reverse immunosuppression, and induce tertiary lymphoid structures (TLS) within the glioma microenvironment (GME) to enhance natural and adaptive immune responses. We successfully induced antigen-presenting cell activation, macrophage/microglia polarization, and TLS formation in GME by intracranial delivery of BafA1@Rexo-SC, which comprises exosomes from irradiated bone marrow-derived stem cells overexpressing CD47 nanobodies and STING, loaded with the autophagy inhibitor BafA1. These exosomes efficiently activated the cGAS-STING pathway, leading to the formation of "lymphoid tissue organizer cells (Lto)" cells, VEGFA release for high endothelial microvessel formation, and chemokine release for T and B cell recruitment. BafA1@Rexo-SC also promoted macrophage phagocytosis of tumor cells and enhanced effector T cell function by blocking CD47, while releasing type I interferon. Our findings suggest novel therapeutic approaches for glioma treatment.