Altered fatty acid metabolism drives glioblastoma growth and treatment resistance

Glioma is the most common primary malignant brain tumor in adults, and glioblastoma (GBM), particularly IDH (Isocitrate dehydrogenase)-wildtype disease, has the poorest prognosis. Median overall survival for GBM is approximately 14 to 16 months. Standard treatment for GBM combines maximal safe tumor resection with radiotherapy and chemotherapy, yet many tumors remain resistant. This treatment-resistance behavior of GBM highlights the gap to identify innovative treatment strategies.

Previous studies indicate that cancer cells can rewire the metabolism to sustain growth and resist treatment. One such rewiring approach is the fatty acid metabolism that supplies energy and support membrane structures, while influencing cellular signaling and immune activity. Although substantial evidence exist on the fatty acid metabolism, studies elucidating its underlying molecular mechanisms remain limited.

Addressing this gap, a research team led by Dr. Wei Zhang and Dr. Guanzhang Li from the Department of Neurosurgery, Capital Medical University, People's Republic of China, reviewed how altered fatty acid metabolism contributes to glioma development and treatment responses. The review examines fatty acid synthesis, transport, storage, breakdown, and elongation, and their effects on tumor growth, invasion, angiogenesis, the tumor microenvironment, and treatment resistance. This paper was published in Volume 12 of the Chinese Neurosurgical Journal on July 31, 2026.

Abnormal fatty acid metabolism can connect tumor growth with treatment resistance and changes in the immune environment."

Dr. Wei Zhang, Department of Neurosurgery, Capital Medical University, People's Republic of China

Fatty acid metabolism does more than fuel tumor cells. Fatty acids build cell membranes and produce signaling molecules that influence proliferation and inflammation. The study focuses on regulators including fatty acid synthase (FASN), fatty acid-binding protein 7 (FABP7), and enzymes involved in protein palmitoylation.

FASN, which helps cells produce fatty acids, is linked to processes that may complicate GBM treatment. After radiotherapy, glioma cells can accumulate unsaturated fatty acids and lipid droplets that may relieve stress and support survival. FASN-associated signaling has also been linked to microglia recruitment and an immunosuppressive tumor environment. FABP7 transports fatty acids and can influence gene regulation, tumor cell proliferation, and glioma stem cell migration. Other targets may contribute differently; stearoyl-CoA desaturase 1 (SCD1) is associated with temozolomide resistance, potential association of diacylglycerol acyltransferase 1 (DGAT1) with radioresistance, and monoacylglycerol lipase (MAGL) with stem cell self-renewal and immunosuppressive macrophage activity.

The study highlights clinical trials that are experimenting potential treatment strategies. In a phase II trial involving patients with recurrent high-grade astrocytoma, the FASN inhibitor TVB-2640 combined with bevacizumab was associated with a 6-month progression-free survival rate of 31.4%, compared with a historical rate of 16% for bevacizumab alone. A phase III trial of an FASN inhibitor with bevacizumab for recurrent GBM is ongoing, but results have not been published. The researchers also discuss preclinical findings involving DGAT1 inhibition and strategies targeting epidermal growth factor receptor (EGFR) signaling and fatty acid synthesis.

"Combining metabolic interventions with established treatments may help address resistance, but these approaches need careful testing," Dr. Li says.

Important hurdles remain before these findings can translate into routine care. Most proposed targets are supported mainly by preclinical evidence, and disrupting lipid metabolism could also affect neurons and immune cells. The blood-brain barrier limits delivery of many medications to gliomas. Future research must establish which patients may benefit, distinguish tumor-specific targets from those in healthy tissue, and develop safe drug-delivery methods.

Overall, the review presents fatty acid metabolism as a promising research area, not an established glioma treatment. By clarifying how lipid pathways interact with tumor behavior, immune responses, and standard therapies, it provides a framework for studying the combination treatments. Clinical validation will be essential to determine whether these strategies improve outcomes for people with glioma.