Metabolic Modulation of Glioblastoma by Dietary Intervention: A Systematic Review

BackgroundGlioblastoma (GBM) is characterized by aggressive clinical behavior and profound resistance to conventional therapies. As a result, non-pharmacologic strategies that exploit tumor metabolic vulnerabilities, particularly dietary interventions, are gaining attention. Ketogenic diets (KD) and methionine restriction (MR) aim to disrupt tumor bioenergetics and epigenetic regulation by modifying systemic nutrient availability. ObjectiveTo systematically evaluate preclinical and clinical evidence on the efficacy, safety, and mechanistic rationale of KD and MR in glioma treatment. MethodsWe conducted a systematic review of PubMed and Embase (through June 10, 2025), including preclinical and clinical studies involving KD or MR in gliomas. Eligible studies included in vivo preclinical models and clinical trials involving high grade gliomas. Data on study design, intervention characteristics, outcomes (survival, metabolic biomarkers, feasibility), and proposed mechanisms were extracted and synthesized narratively. ResultsA total of 31 studies were included: 10 preclinical and 13 clinical for KD; 6 preclinical and 2 clinical for MR. Preclinical studies demonstrated consistent anti-tumor effects, including survival prolongation and metabolic disruption, particularly when combined with radiotherapy or chemotherapy. Clinical outcomes were variable. KDs were feasible and well-tolerated, though adherence varied and survival benefits were inconsistent. MR showed promising metabolic effects and some clinical responses, but trials were limited by small sample sizes and high toxicity when combined with chemotherapy. ConclusionDietary interventions such as KD and MR target critical metabolic vulnerabilities in gliomas and show strong preclinical rationale. However, clinical translation is challenged by tumor heterogeneity, metabolic adaptability, and dietary adherence. Future trials should incorporate metabolic imaging, flux analysis, and cross-disciplinary strategies to optimize and personalize dietary therapies as adjuncts in glioma care.