Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands.
Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands.
Cell. 2024 Sep 19;187(19):5336-5356.e30. doi: 10.1016/j.cell.2024.07.030. Epub 2024 Aug 12.
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.
在代谢受到挑战的环境中生长的肿瘤，如大脑中的神经胶质瘤，特别依赖于与肿瘤微环境 (TME) 的相互作用来满足其高能量需求。为了研究这种代谢相互作用的复杂性，我们使用单细胞和多组学分析研究了神经胶质瘤 TME 的异质性，并鉴定出具有促肿瘤特性的代谢重编程的肿瘤相关巨噬细胞 (TAM) 亚群。这些 TAM 亚群被称为富含脂质的巨噬细胞 (LLM)，以反映其胆固醇积累，它们在表观遗传上被重新布线，表现出免疫抑制特征，并在侵袭性间充质神经胶质瘤亚型中富集。富含胆固醇的髓磷脂碎片的吞噬赋予了 TAM 的子集获得 LLM 表型的能力。随后，LLM 以 LXR/Abca1 依赖的方式将髓磷脂衍生的脂质直接转移到癌细胞中，从而为间充质神经胶质瘤的代谢需求提供燃料。我们的工作深入了解了神经胶质瘤进展过程中的免疫代谢相互作用，从而为揭示神经胶质瘤的可靶向代谢脆弱性奠定了框架。
