Pallares Moratalla, C.; Guyot, M.; Gopalan, K. S.; Robl, B.; Idkowiak, J.; Dehairs, J.; Ravoet, N.; Nowak, K. A.; Dubroja, N.; Weng, L.; Konstantakos, V.; Spotbeen, X.; Fendt, S. M.; Aerts, S.; De Smet, F.; Swinnen, J. V.; Bergers, G.

Glioblastoma (GBM) is characterized by diffuse infiltration into the surrounding brain, which precludes complete surgical resection, the strongest determinant of patient survival. The mechanisms that drive this invasive growth remain incompletely understood. Here we identify a lipid-mediated paracrine signaling axis through which microglia, the resident macrophages of the brain, promote glioma invasion. Integrating single-cell transcriptomics, spatial lipidomics, and functional perturbation across mouse models and human GBM samples, we show that invading tumor cells engage and reprogram microglia via CSF1R/PI3K signaling. This induces a metabolic switch in microglia, leading to the secretion of bioactive lipids, including lysophosphatidylcholines (LPCs) and lysophosphatidic acids (LPAs), which act as pro-invasive cues across GBM subtypes through distinct downstream pathways. Disruption of the microglia/GBM axis, either by inhibiting CSF1R signaling or by blocking lipid mobilization, reduces lipid secretion and suppresses tumor invasion. Targeting downstream LPA/LPAR or YAP/TAZ signaling further constrains invasion in a context-dependent manner. Together, these findings define a lipid-driven signaling circuit that links the tumor microenvironment to glioma invasion and identify therapeutic strategies to limit tumor infiltration and improve surgical resectability.