Lipid metabolic plasticity in glioblastoma: mechanisms, tumor microenvironment remodeling, and therapeutic opportunities

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor and remains associated with poor prognosis despite multimodal treatment. Increasing evidence indicates that lipid metabolic reprogramming is a critical hallmark of GBM progression and therapeutic resistance. Beyond supporting membrane biosynthesis and energy production, dysregulated lipid metabolism profoundly influences tumor plasticity, oxidative stress adaptation, immune suppression, stemness maintenance, and ferroptosis sensitivity within the tumor microenvironment. GBM cells dynamically rewire lipid metabolic pathways through enhanced de novo lipogenesis, fatty acid uptake, cholesterol remodeling, lipid droplet accumulation, and fatty acid oxidation to adapt to hypoxia, nutrient deprivation, and therapeutic stress. In parallel, lipid metabolic interactions between tumor cells and immune components, including tumor-associated macrophages and exhausted T cells, further contribute to immunosuppressive microenvironment formation and resistance to chemotherapy, radiotherapy, and immunotherapy. Recent advances in spatial transcriptomics, single-cell metabolomics, and multi-omics integration have substantially improved understanding of lipid metabolic heterogeneity in GBM. These emerging technologies have also facilitated the identification of novel metabolic vulnerabilities and therapeutic targets. In this review, we summarize current insights into lipid metabolic plasticity in GBM and discuss the mechanistic links between lipid metabolism, tumor microenvironment remodeling, ferroptosis regulation, and therapeutic resistance, highlighting potential opportunities for precision metabolic therapy in GBM.