Reactive oligodendrocytes promote glioblastoma progression through CCL5/CCR5-mediated glioma stem cell maintenance

Glioblastoma (GBM) evolves within a microenvironment abundant in oligodendrocyte-lineage (OL) cells. In this study, we utilized single-cell and spatial transcriptomics from primary and recurrent GBM tumors, immunohistochemistry, cytokine profiling, and migration assays to show that GBM cells recruit OLs to the tumor border via fractalkine (i.e., CX3CL1/CX3CR1) signaling. A pan-disease human OL meta-atlas and syngeneic mouse models reveal an interferon (IFN)-induced reactive OL state, akin to those seen in demyelinating inflammatory and traumatic injury, which is enriched in central nervous system malignancies. These reactive OLs secrete pro-tumorigenic cytokines, notably C-C motif chemokine ligand 5 (CCL5), that promote GBM tumor cell growth through C-C chemokine receptor type 5 (CCR5) signaling. CCR5 is preferentially expressed in glioma stem-like cells (GSCs) and upregulated at recurrence. Targeting CCR5 with genetic knockdown or the approved drug maraviroc impairs GSC stemness and prolongs survival in GBM models. Our work highlights the functional interplay between OLs and GBM cells and positions the CCL5/CCR5 axis as a druggable target in GBM.