The Unsaturated/Saturated Fatty Acid Ratio: A Metabolic Hub and Therapeutic Vulnerability in Glioblastoma

Abstract

Glioblastoma (GBM) exhibits profound metabolic reprogramming, among which the balance between unsaturated and saturated fatty acids (UFA/SFA) emerges as a critical determinant of tumor behavior and treatment response. Recent studies have shown that fatty acid metabolic reprogramming is a key mechanism driving GBM progression. Abnormalities in fatty acid uptake, synthesis, desaturation, and oxidation collectively reshape the lipid composition of tumor cells, particularly by altering the unsaturated/saturated fatty acid ratio. Monounsaturated fatty acids mainly promote tumor cell proliferation and membrane biosynthesis, polyunsaturated fatty acids can induce lipid peroxidation and ferroptosis under specific stress conditions, whereas excessive saturated fatty acids can cause lipotoxicity when desaturation is limited. Key enzymes in fatty acid metabolism constitute a regulatory network and provide potential therapeutic targets for GBM. In addition, fatty acid metabolism can remodel the tumor immune microenvironment, especially by affecting the functional state of tumor-associated macrophages. Rather than targeting a single lipid species or isolated metabolic enzyme, therapeutic strategies that recalibrate the UFA/SFA ratio may provide a more integrated approach to restraining GBM progression and improving treatment sensitivity.