Paracrine TMSB4X signaling from oligodendrocytes promotes diffuse glioma dissemination

White matter invasion underlies the lethality of diffuse glioblastoma (GBM), yet its microenvironmental drivers remain poorly defined. Here, we demonstrate that tumor-oligodendrocyte (OL) crosstalk actively promote white matter-associated glioma expansion. In the primary GBM or white matter-invasive glioma, OL lineage cells accumulate at tumor borders and enhance glioma proliferation and migration via secreted factors. Proteomic analysis combined with RNA sequencing identifies OL-derived TMSB4X (thymosin β-4) activates AKT signaling to sustain tumor expansion and invasion. Furthermore, glioma-derived TGF-β stimulates OL differentiation and TMSB4X production, establishing a feed-forward circuit that reinforces tumor progression. Critically, genetic or pharmacological blockade in tumor-OL interaction attenuates glioma outspreading along the white matter in vivo. These findings redefine the OLs as pro-invasive modulators and suggest OL-glioma crosstalk as a therapeutic target in diffuse GBM. Glioblastoma spreads through the brain's white matter while hijacking nearby oligodendrocytes. These cells release TMSB4X, which activates AKT signaling in tumor cells and promotes growth and invasion. In turn, tumors secrete TGF-β, which stimulates oligodendrocytes to produce more TMSB4X. This feed-forward loop may offer a new therapeutic target to prevent glioma from invading the white matter after surgical resection.