Cancer metabolism has evolved from a descriptive feature to a therapeutic target integrating oncogenic signaling, tissue constraints, and immune regulation. Metabolic reprogramming can meet biosynthetic demands under fluctuating nutrition and oxygen, maintain redox homeostasis while preserving mitochondrial function, and shape an immunosuppressive tumor microenvironment through metabolite gradients, acidity, and substrate competition. This review summarizes the major metabolic modules that sustain malignant progression, including: glucose utilization and its lactate-driven ecosystem effects; lipid metabolic remodeling that couples fatty acid oxidation to mitochondrial dynamics and translocation behavior; amino acid-dependent enhancements of thiol buffering and ferroptosis resistance; and mitochondrial energy programs that enable adaptive switching under therapeutic stress. Emerging metabolic-targeted therapies are categorized, encompassing inhibition of nutrient signaling pathways and hypoxia adaptation, lipid and amino acid-directed interventions that disrupt buffering circuits, and strategies that inhibit mitochondrial quality control. A recurring theme is that therapeutic efficacy is often limited by metabolic plasticity, which is enhanced by autophagy, stress response signaling, and synergistic adaptations among the tumor, matrix, and immune system. Therefore, delivery innovation has become a mechanistic determinant, as antibody-drug conjugates, prodrug structures, catalytic nanoreactors, and biomimetic carriers can localize metabolic stress, amplify reaction chemistry, and promote the co-localization of co-perturbations. Finally, rational combination regimens with chemotherapy, targeted therapy, and immunotherapy are discussed, aiming to prevent compensatory reprogramming while transforming the metabolically inhibited microenvironment into an immune-allowed state.
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