Microglia-derived Small Extracellular Vesicles Promote Bone Marrow Monocyte Expansion and Recruitment in Glioblastoma.

Abstract

Glioblastoma (GBM) remains one of the deadliest human cancers and is characterized by a profoundly immunosuppressive tumor microenvironment (TME). Although tumor-associated microglia (TAMg) promote GBM progression, their role in regulating immune cell recruitment remains poorly understood. Here, we demonstrate that TAMg-derived small extracellular vesicles (sEVs) mediate bone marrow-derived monocyte recruitment into the GBM TME. We find that these sEVs traffic to the bone marrow, where they selectively target monocytes and their progenitors. Mechanistically, sEV internalization activates MAPK signaling and inflammatory transcriptional programs, driving the differentiation and expansion of inflammatory monocytes. Together, our findings establish microglia-derived sEVs as a previously unrecognized mechanism of communication between the GBM TME and the peripheral immune system, thereby promoting the establishment of an immunosuppressive TME that drives GBM progression.