Ketogenic diet as a systems-level immunometabolic sensitization strategy in cancer therapy: integrating metabolism, immune reprogramming, microbiome dynamics, and epigenetic regulation

Abstract The ketogenic diet (KD) is increasingly being recognized as more than a simple metabolic intervention in cancer therapy. Emerging evidence suggests that KD may function as a systems-level immunometabolic sensitization strategy capable of enhancing therapeutic responsiveness through interconnected biologic mechanisms. Modern cancer therapies, including chemotherapy, targeted therapy, radiotherapy, and immunotherapy, are often limited by tumor adaptability and immune suppression. Tumors shift metabolism via the Warburg effect and fuel switching, promoting resistance under hypoxic and nutrient stress. KD is a high-fat and low-carb eating plan that increases ketone bodies such as β-hydroxybutyrate while lowering glucose availability. Under ketogenic conditions, cancer cells reduce glycolytic flux, while immune cells can oxidise ketones to sustain mitochondrial function and effector activity. KD also remodels the gut microbiome and induces epigenetic regulation through histone deacetylase inhibition. These combined effects may enhance chemotherapy, radiotherapy, targeted therapy, and immunotherapy by inducing metabolic stress, improving immune cell fitness, and altering tumour microenvironment signaling. Importantly, KD may function not as a standalone treatment but as a therapy-sensitization platform. However, current evidence remains preliminary and heterogeneous, and further mechanistic investigations and well-designed prospective clinical trials are necessary to determine optimal patient selection and long-term safety.