The metabolic properties of cancer cells differ significantly from those of normal cells, with a notable dependency on aerobic glycolysis, increased fatty acid synthesis, and enhanced glutamine metabolism. These metabolic characteristics are linked to therapeutic resistance in cancer treatment. Targeting metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase, and glutaminase, can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy and radiotherapy. The review discusses the relationship between dysregulated cellular metabolism and cancer drug resistance, highlighting how targeting metabolic enzymes can improve cancer therapeutics. Key mechanisms include ATP depletion, increased drug accumulation, and promotion of apoptosis. Combining chemotherapeutic agents with metabolic inhibitors represents a promising strategy to overcome drug resistance and improve treatment outcomes.The metabolic properties of cancer cells differ significantly from those of normal cells, with a notable dependency on aerobic glycolysis, increased fatty acid synthesis, and enhanced glutamine metabolism. These metabolic characteristics are linked to therapeutic resistance in cancer treatment. Targeting metabolic enzymes, such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase, and glutaminase, can enhance the efficacy of common therapeutic agents or overcome resistance to chemotherapy and radiotherapy. The review discusses the relationship between dysregulated cellular metabolism and cancer drug resistance, highlighting how targeting metabolic enzymes can improve cancer therapeutics. Key mechanisms include ATP depletion, increased drug accumulation, and promotion of apoptosis. Combining chemotherapeutic agents with metabolic inhibitors represents a promising strategy to overcome drug resistance and improve treatment outcomes.