β‐Hydroxybutyrate in Cancer: From Alternative Fuel to a Context‐Dependent Metabolic Signal

ABSTRACT β‐Hydroxybutyrate ( BHB ) is the primary circulating ketone body generated during fasting, prolonged exercise, carbohydrate restriction, and ketogenic diets. Beyond functioning as an alternative oxidative substrate, BHB engages in HCAR2 ‐mediated signaling, HDAC ‐related regulation, redox coupling, and lysine β‐hydroxybutyrylation, thus influencing tumor cell metabolism, chromatin state, and the tumor immune microenvironment. The biological effects of BHB in cancer exhibit high context dependency. In certain models, BHB inhibits inflammation, angiogenesis, epithelial‐mesenchymal transition, or tumor growth, while in others, it promotes metabolic adaptation, survival, metastasis, or treatment resistance. These seemingly contradictory outcomes can be elucidated through two major mechanistic switch points. The first involves tumor cell ketolytic competence: cells exhibiting effective BHB uptake, functional BDH1 – OXCT1 ‐dependent ketolysis, and preserved mitochondrial respiration may utilize BHB as an adaptive substrate under nutrient or therapeutic stress. The second concerns cellular allocation within the tumor microenvironment, determining whether BHB preferentially supports malignant cells, antitumor lymphocytes, or other immune and stromal populations. Furthermore, BHB source and treatment context further modulate these responses. Notably, ketogenic diet, direct BHB supplementation, and tumor‐intrinsic ketogenesis represent biologically distinct experimental states and should not be interpreted interchangeably. This review integrates current evidence into a source–access–interpretation framework that differentiates tumor‐adaptive, signaling‐dominant, and immune‐supportive BHB states, emphasizing priorities for causal, cell‐resolved, and biomarker‐guided investigation.