LAUSR

Glioblastoma (GBM) is characterized by extensive neovascularization and a highly immunosuppressive microenvironment. GBM-associated microglia and macrophages (GAMs) constitute the major immune cell population and are key drivers of tumor growth and immunosuppression. However, the mechanisms by which GAMs acquire a pro-tumorigenic phenotype are poorly understood. In this study, we found that GBM-associated vascular cells (GVCs) show increased expression of pro-tumorigenic and anti-inflammatory cytokines known to influence the function and polarization of macrophages. Notably, conditioned medium (CM) from GVCs induced polarization of microglia towards an M2-like immunosuppressive phenotype. Transcriptomic analysis of GVC-reprogrammed microglia revealed significant enrichment of inflammatory gene signatures and increased expression of immunosuppressive markers and cytokines. Differential gene expression analysis showed upregulation of store-operated calcium channels (SOCC), mainly ORAI1 and ORAI3. Microglia cultured in GVC-CM showed increased protein expression of ORAI1 and ORAI3 and intracellular Ca²⁺ levels. Pharmacological inhibition of ORAI1 and ORAI3 channels in microglia reversed the immunosuppressive phenotype induced by GVC-CM and reduced the growth of GBM cells. Together, these findings indicate an important role for SOCC in mediating the GVC-induced immunosuppressive phenotype of microglia in GBM.