Dietary polyphenols and nutritional modulators in glioblastoma: mechanistic promise and translational barriers.

Glioblastoma is the deadliest primary brain tumor, and fewer than 7% of patients survive 5 years even after surgery, radiation, and chemotherapy. Several features make it difficult to treat: the tumor heterogeneity, it adapts quickly to resist drugs, and the blood-brain barrier keeps most agents from reaching it. These obstacles have renewed interest in adjuncts to standard care. Dietary polyphenols and certain nutritional compounds are among the candidates, since they can influence oxidative stress, inflammation, tumor metabolism, and the glioblastoma stem cells that drive recurrence. This review weighs the mechanistic, preclinical, and early clinical evidence for major polyphenols (curcumin, resveratrol, EGCG, quercetin, apigenin), non-polyphenol agents (omega-3 fatty acids, vitamin D, melatonin), and dietary patterns such as ketogenic, anti-inflammatory, and caloric restriction approaches. Across models these agents act on familiar oncogenic and stress pathways, including NF-κB, STAT3, PI3K/AKT/mTOR, and MAPK, curbing proliferation and invasion, triggering apoptosis, and sensitizing tumors to temozolomide and radiation. What the laboratory shows has rarely reached patients. Poor oral absorption, inconsistent brain penetration, heavy first-pass metabolism, individual variability, and a shortage of biomarker-guided trials stand in the way. We do not propose these agents as substitutes for treatment. Instead, we connect their biological promise to the pharmacokinetic, delivery, and trial design problems that decide whether they can ever help, treating them strictly as experimental adjuncts. By covering polyphenols, other nutritional agents, and whole dietary patterns together, the review offers a translational picture that earlier reviews have missed.