Abnormal energy metabolism is one of the fundamental features of cancer. Although targeting cancer metabolism is a promising therapeutic strategy clinical treatment success depends on accurate molecular and metabolic subtyping. Recent studies have reported two metabolism-based molecular subtypes associated with cancer ketogenic treatment glycolytic glycolysis + / ketolysis - and ketolytic glycolysis + / ketolysis + which were manifested by distinct metabolic enzyme profiles and mitochondrial functional states and by different responses to ketogenic interventions in vitro and in vivo. Notably in p53-mutated tumors the glycolytic subtype was able to be converted to the ketolytic subtype upon glucose limitation rendering resistance to ketogenic therapy associated with upregulation of the ketolytic enzyme and mitochondrial fusion process. However the allosteric activator of mutant p53 can effectively block the rewired molecular expression and the reprogrammed mitochondrial metabolism by conjugating mutant p53 to a wild-type conformation thus maintaining a stable ketolytic-deficient phenotype. Based on the metabolic subtypes the target population of cancer ketogenic therapy can be decided and the sensitivity of ketogenic treatment can be predicted by the mutation status thus establishing a strategy of precise cancer metabolic modulation therapy.