Ketogenic Diet as an Adjuvant in Epithelial Cancers: Mechanisms, Model Systems, and Translational Opportunities.

Ketogenic metabolic therapy (KMT), typically implemented as a ketogenic diet (KD), has re-emerged as a potential adjuvant strategy in oncology. Its rationale is grounded in the metabolic reprogramming of cancer cells, including their reliance on glucose and lipid substrates and the signaling functions of ketone bodies. Despite extensive preclinical evidence of anti-proliferative and immunomodulatory effects, clinical translation in cancer therapy has been slow and inconsistent. This review critically examines the mechanistic basis, experimental and clinical evidence, and translational challenges of KMT across epithelial cancers. We emphasize that "ketogenic interventions" comprise mechanistically distinct modalities, including classical KD, fasting, fasting-mimicking diets, and exogenous ketone supplementation, which are frequently conflated yet differ substantially in their endocrine and metabolic contexts. Across clinical studies, KMT is generally feasible and associated with improvements in quality of life and metabolic parameters; however, robust evidence for the survival benefit of KMT remains limited and heterogeneous. Mechanistically, ketone bodies exert both metabolic and signaling functions, including inhibition of histone deacetylases, lysine β-hydroxybutyrylation, and receptor-mediated effects. Tumor responses are highly context-dependent: ketolytic capacity, governed by enzymes such as OXCT1, can render ketones either a metabolic vulnerability or an alternative fuel for cancer cells. KMT can modify the complex tumor microenvironment, exerting potentially opposing effects on cancer cells, immune cell populations, fibroblasts, and adipocytes. We argue that the central limitation of the field is not a lack of biological activity, but of insufficient integration of tumor-intrinsic metabolism, host physiology, and microenvironmental context. KD/KMT should therefore be regarded not as a universal anticancer therapy, but as a stratified metabolic intervention, whose progress will depend on biomarker-guided patient selection, improved experimental models, and rational combination strategies within a "press-pulse" therapeutic framework.