Lipid metabolic regulation and targeting strategies in the brain metastasis tumor microenvironment

Brain metastasis is a major contributor to poor prognosis in cancer patients, with therapeutic efficacy severely constrained by the blood-brain barrier and the complex brain microenvironment. Although lipid metabolic reprogramming has been linked to tumor progression across multiple cancer types, its mechanistic involvement in brain metastasis, particularly its reciprocal interactions with central nervous system microenvironmental cells, remains insufficiently defined. This review synthesizes existing evidence to elucidate how lipid metabolic reprogramming promotes tumor cell colonization and growth in the brain and to evaluate its therapeutic relevance. Current findings indicate that metastatic tumor cells adapt to the brain microenvironment via increased de novo lipogenesis, altered cholesterol metabolism, reduced fatty acid oxidation, and enhanced uptake of exogenous lipids. Emerging evidence further indicates reciprocal lipid-metabolic interactions between metastatic tumor cells and central nervous system-resident cells; however, the directionality, cell-type specificity, and underlying molecular mechanisms of this metabolic crosstalk remain insufficiently characterized. Such interactions may promote immunosuppressive microenvironmental remodeling and facilitate metastatic progression. Significant heterogeneity is observed among primary tumor types in their use of lipid metabolism associated mechanisms. Targeting critical nodes at the interface of lipid metabolic reprogramming and microenvironmental interactions may therefore help overcome current therapeutic limitations in brain metastasis. Future studies using advanced multi-omics approaches are expected to define spatial heterogeneity and support the development of combination strategies capable of crossing the blood-brain barrier, ultimately informing improved clinical management strategies.