Neuro-Oncology · Nov 2026
TMIC-09 Investigating lipid metabolism coupling between microglia and glioblastoma
By Bufi R, Mayo CB, Oliveira NADJ et al.
Abstract Glioblastoma (GBM) remains the most lethal primary brain malignancy, with median survival under 15 months despite multimodal therapies. Its incidence peaks at 75 years and prognosis worsens with age, yet the mechanistic link between aging and GBM lethality remains unexplored. In the aging brain, white matter degradation generates myelin debris that overwhelms microglial phagocytic capacity, causing chronic lipid accumulation within aged microglia. To manage this overload, aged lipid-droplet accumulating microglia (LDAM) upregulate cholesterol efflux pathways to help offload their lipid burden. Interestingly, macrophages and microglia together comprise up to 50% of GBM tumor mass but adopt dysfunctional phenotypes rather than mounting anti-tumor responses. Tumor-associated macrophages (TAMs) that phagocytose myelin debris strikingly acquire similar lipid-laden phenotypes and exploit the same cholesterol efflux pathways to transfer myelin-derived lipids to GBM cells, fueling proliferation and invasion. To dissect whether age-associated, myelin-induced changes in microglial lipid metabolism drive GBM growth in an analogous manner, we developed a co-culture system combining myelin-loaded induced pluripotent stem cell (iPSC)-derived microglia (iMG) with patient-derived glioma stem cells (GSCs). Our work shows that iMG recapitulate critical LDAM phenotypes when exposed to myelin debris, including myelin scavenging, lipid droplet formation, and decreased phagocytic capacity under myelin overload. Co-culture of myelin-loaded iMG with GSCs reveals changes in GSC phenotype that suggest a role for microglial lipid metabolism in fueling tumor cell growth. By defining how LDAM metabolically couple with GSCs, this work will reposition aging from a passive risk factor to an active driver of GBM progression, motivating metabolic therapies that target age-specific vulnerabilities in the tumor microenvironment. Targeting the tumor’s fuel supply rather than the tumor itself offers a path forward for elderly patients with GBM, who remain the most underserved by current therapies.