Ketogenic Diet: A Metabolic Key to Overcoming Cancer Therapy Resistance

The ketogenic diet (KD), characterized by very low carbohydrate intake, moderate protein consumption, and variable fat content depending on the specific dietary protocol, has emerged as a promising metabolic approach in oncology. Although significant progress has been achieved in chemotherapy and immunotherapy for cancer treatment, it still faces challenges in terms of resistance to drugs, systemic toxicity, and immunosuppressive microenvironments of tumor tissues. The KD has been reported to exploit the metabolic weaknesses of tumor cells, such as glycolytic addiction and mitochondrial rigidity, while sparing normal tissue metabolism. The anticancer effects of KD are linked to metabolic and signaling reprogramming that may increase tumor sensitivity to treatment. The ketone bodies, especially β-hydroxybutyrate, play a significant role in tumor metabolism and stress response through histone deacetylase inhibition, anti-inflammatory properties in normal tissues, and modulation of chemotherapy-induced toxicity. A large body of preclinical data supports the use of KD to enhance the efficacy of chemotherapeutic agents, such as cisplatin, doxorubicin, temozolomide, and gemcitabine, through mechanisms that include redox imbalance, inhibition of DNA repair, and induction of apoptosis in tumor cells. Emerging experimental data also indicate that KD may affect the tumor immune microenvironment by modulating effector and suppressive immune cells and by interacting with immune checkpoint therapy. However, the translation of these data into the clinic is heterogeneous. Early-phase clinical trials and feasibility studies in glioblastoma, breast, colorectal, and pancreatic cancers have shown that KD is feasible in the clinic and that some benefits in metabolic parameters and quality of life are observed, but evidence of anticancer activity remains limited. Importantly, the response to KD in the clinic seems to depend on the formulation and implementation of the dietary intervention, including the use of high-fat KDs versus very-low-calorie ketogenic diets (VLCKDs), as well as the metabolic context in which the intervention is performed, including obesity and insulin resistance. Overall, current data support KD as a biologically plausible and hypothesis-generating immunometabolic strategy that warrants further evaluation in well-designed, controlled clinical trials with careful attention to dietary composition, metabolic phenotype, safety, and patient adherence.