在代谢困难的环境中生长的肿瘤（例如大脑中的胶质母细胞瘤）特别依赖于与其肿瘤微环境（TME）的串扰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，我们利用单细胞和多组学分析探讨了胶质母细胞瘤 TME 的异质性，并鉴定了具有促肿瘤特性的代谢重组肿瘤相关巨噬细胞 (TAM) 亚群。这些 TAM 子集被称为脂质巨噬细胞 (LLM)，以反映其胆固醇积累，它们经过表观遗传重新连接，显示出免疫抑制特征，并且富含侵袭性间充质胶质母细胞瘤亚型。富含胆固醇的髓磷脂碎片的吞噬赋予 TAM 子集以获得 LLM 表型。随后，LLM 以 LXR/Abca1 依赖性方式直接将髓磷脂衍生的脂质转移至癌细胞，从而刺激间充质胶质母细胞瘤的代谢需求增加。我们的工作提供了对胶质母细胞瘤进展过程中免疫代谢相互作用的深入了解，从而奠定了揭示胶质母细胞瘤中可靶向代谢脆弱性的框架。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.