Single-cell and spatial transcriptomes reveal oligodendrocyte remodeling fatty acid metabolism microenvironment of...

Brain metastases represent a prevalent and lethal complication in advanced lung cancer, where the brain microenvironment is pivotal in facilitating metastatic tumor progression. Recent findings indicate the presence of oligodendrocyte infiltration within lung cancer brain metastases (LCBM). Lipid metabolic reprogramming has emerged as a critical feature of the brain metastatic niche, influencing both tumor cell survival and immune cell function. This study aimed to determine whether oligodendrocytes undergo lipid metabolic reprogramming in LCBM and whether their derived fatty acids functionally promote tumor proliferation and immune modulation.

Single cell RNA sequencing (ScRNA-seq), spatial transcriptome sequencing, lipidomics, and lipid tracing techniques to comprehensively analyze metabolic alterations in oligodendrocytes and their dynamic interactions with tumor and immune cells. Western blotting, qPCR and multiple immunofluorescence staining were used to detect the expression of fatty acid synthesis enzymes in oligodendrocytes and immunosuppressive markers in macrophages.

Analysis of independent scRNA-seq datasets revealed markedly increased lipid synthesis activity in oligodendrocytes within LCBM. Hypoxic conditions and co-culture with metastatic lung cancer cells further enhanced the expression of fatty acid synthases in oligodendrocytes. Spatial transcriptomics and scRNA-seq indicated that tumor cells and macrophages were major recipients of oligodendrocyte-derived fatty acids, exhibiting enhanced uptake and degradation. Treatment with oligodendrocyte-conditioned medium significantly increased the expression of fatty acid uptake proteins in tumor cells and macrophages. Furthermore, oligodendrocyte-derived fatty acids supported tumor cell proliferation and polarized macrophages toward an immunosuppressive phenotype. Notably, scRNA-seq identified a macrophage subpopulation (Mac_FABP4) as a candidate mediator of lipid-driven immune suppression.

These findings delineate the pivotal role of oligodendrocytes in LCBM, revealing their contribution of lipids that enhance tumor proliferation and induce immunosuppression, thereby suggesting that glial lipid metabolism may represent a potential therapeutic target warranting further investigation.