Targeting metabolic mechanisms to overcome temozolomide resistance in glioblastoma

Temozolomide (TMZ) resistance remains a major clinical obstacle in the treatment of glioblastoma (GBM), a highly aggressive brain tumor with poor prognosis. Growing evidence showed that metabolic reprogramming contributed to TMZ resistance and offered new avenues for intervention. This review comprehensively summarizes resistance-associated changes across three key areas – glycolysis, redox homeostasis, and lipid metabolism in TMZ-resistant GBM. The resistant cells tend to display enhanced glycolytic flux, with upregulation of glucose transporter and glycolysis enzymes. To counteract TMZ-induced oxidative stress, antioxidant systems are activated. Lipid metabolism is also extensively rewired, involving increased fatty acid oxidation, de novo lipogenesis, steroid hormone synthesis, and prostaglandin E₂-mediated signaling, along with a decreased ceramide level. Emerging preclinical research investigated therapeutic strategies targeting resistance-associated metabolic changes to reverse TMZ efficacy. Though preclinical research showed encouraging results, further validation in clinical settings is still needed. A deeper understanding of context-specific metabolic adaptations helps better elucidate the role of metabolism in resistance and to identify therapeutic opportunities with greater clinical translational potential.