Macrophage-mediated myelin recycling fuels brain cancer malignancy

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma. [Display omitted] •TAMs recycle cholesterol-rich myelin, acquiring lipid-laden features in glioblastoma•Epigenetic rewiring induced by myelin debris scavenging underlies LLM immunosuppressive features•LLMs transfer myelin-derived lipids to glioblastoma cells to fuel disease progression•LLMs correlate with aggressive mesenchymal subtype and poor prognosis in patients Recycling of cholesterol-rich myelin debris by macrophages leads to the emergence of lipid-laden macrophages (LLMs) in glioblastoma. LLMs support glioblastoma malignancy through transfer of myelin-derived lipids to tumor cells, fueling cancer cell proliferation and recurrence.