Nutritional approaches in combating therapeutic resistance and enhancing treatment efficacy in cancer: the impact of ketogenic diets.

Cancer remains a major global health challenge, with therapeutic resistance significantly limiting treatment success. Traditional approaches, including surgery, chemotherapy, and radiotherapy, often encounter barriers such as metastasis and adverse effects on healthy tissues. The Warburg effect, which describes cancer cells’ reliance on glucose fermentation despite oxygen availability, has prompted investigations into alternative metabolic interventions. The ketogenic diet (KD), characterized by high fat intake and low carbohydrate intake, induces a metabolic shift that may selectively disadvantage malignant cells while preserving normal tissue function. While emerging evidence, including preclinical studies, early-phase trials, and limited clinical series, suggests that KD may help overcome treatment resistance by suppressing the PI3K/Akt/mTOR pathway, reducing insulin-like growth factor-1 (IGF-1) signaling, and enhancing cancer cell susceptibility to chemotherapy and targeted therapies, robust data from large, randomized controlled trials (RCTs) remain sparse. Most current findings derive primarily from animal models and small pilot studies, with definitive efficacy and safety in broad patient populations yet to be established. Preclinical and preliminary clinical studies indicate KD’s potential in modulating epigenetic markers, reducing inflammation, and improving patient metabolic health. However, patient adherence remains challenging and standardized protocols are still under development. This review explores the molecular mechanisms underlying KD’s anticancer effects, its role in mitigating drug resistance, and current translational insights, with emphasis on the nascent stage of high-quality clinical trial evidence and areas for future research.