Targeting metabolic reprogramming in cancer: Past, present, and future

Cancer cells undergo profound metabolic reprogramming to sustain uncontrolled proliferation within a nutrient-limited and often hypoxic tumor microenvironment (TME). Metabolic rewiring is an active driver of oncogenesis, immune evasion, epigenetic remodeling, and therapy resistance. Over the past century, our understanding of tumor metabolism has grown from Warburg's seminal description of aerobic glycolysis to a comprehensive adaptive network. Cancer cells coordinate glucose catabolism, mitochondrial oxidative metabolism, fatty acid synthesis and oxidation, amino acid catabolism, nucleotide biosynthesis, and one‑carbon metabolism into an integrated metabolic framework. These pathways form a deeply interconnected web in which metabolic intermediates serve as biosynthetic building blocks, bioenergetic substrates, redox buffers, signaling molecules, and epigenetic cofactors. Within the TME, metabolic competition between tumor cells and immune cells, together with the accumulation of immunosuppressive metabolites such as lactate, kynurenine, and adenosine, creates a profoundly immune-hostile landscape. Recent work has further revealed that key post-translational modifications, directly driven by metabolic flux, reshape the chromatin and proteome of both cancer cells and tumor-infiltrating immune cells, linking metabolism to gene regulation in previously unanticipated ways. Therapeutically, the FDA approval of IDH1/IDH2 inhibitors for acute myeloid leukemia demonstrated that metabolic enzymes are tractable oncology drug targets. Yet the broader effort to translate metabolic insights into robust clinical benefit has encountered formidable obstacles, including metabolic plasticity, intratumoral heterogeneity, overlap with normal tissue function, and inadequate biomarkers. This review traces the evolution of our understanding of cancer metabolism from its origins to therapeutic targeting. It further examines how anabolic and catabolic pathways, energy production, redox balance, and metabolic crosstalk across intracellular, intercellular, and systemic domains shape tumor biology and therapeutic response. It also critically analyzes approved and investigational metabolic therapies and charts a course for the emerging era of precision metabolic oncology.