Low carbohydrate high fat diet curbs glioblastoma by shifting lipids and limiting cancer stem cell metabolic flexibility

Metabolic rewiring fuels tumorigenicity of cancer stem cells contributing to universal glioblastoma (GBM) recurrence. Invasive glioblastoma stem cells (GSCs), already unresectable, acquire tumorigenic properties that confer therapy resistance. Using samples from both recurrent and newly diagnosed GBM patients, we identified fatty acid oxidation (FAO) as a key pathway supporting GSC tumorigenicity. Transcriptomic profiling, compared against non-malignant human astrocytes from epilepsy patients, highlighted an FAO-enriched signature in GSCs. In vivo studies showed that tumor formation by these GSCs could be modulated by altering the availability of metabolizable lipids in the brain, with beneficial effects observed under a low carbohydrate high fat diet (LCHFD). The lipid metabolism contributing to GSC mediated tumor formation was confirmed using metabolomic and lipidomic analyses. Gut microbiome analyses revealed that LCHFD shapes the microbiome and modulates the circadian network. By targeting FAO in the postoperative period before chemoradiation, LCHFD offers a non-pharmacologic strategy to delay GBM recurrence. This study suggests a mechanistic framework for dietary modulation as a therapeutic approach to improve GBM outcomes. Low carbohydrate high fat diet restricts lipid availability and limits metabolic capabilities of glioblastoma stem cells to inhibit their contribution towards tumor recurrence.