The Warburg effect, characterized by aerobic glycolysis in cancer cells, represents a metabolic reprogramming mechanism that is critical for sustaining tumorigenesis. In addition to its association with mitochondrial dysfunction, this phenomenon is now recognized as an oncogene-driven adaptation that promotes rapid ATP production, biomass accumulation, and microenvironmental remodeling. Central to glycolytic reprogramming are dysregulated rate-limiting enzymes (including HK2, PFK1/PFKFB3, PKM2, and LDHA), whose activities are regulated by transcriptional networks (e.g. HIF-1α, MYC), post-translational modifications, and isoform switching. Together, these enzymes divert glycolytic intermediates toward anabolic pathways while maintaining redox balance under hypoxic conditions. Tumor progression is further promoted by lactate-mediated extracellular acidification, which reshapes the tumor microenvironment (TME) to promote immunosuppression, angiogenesis, and metastatic dissemination. Glycolytic metabolites also orchestrate epigenetic reprogramming through histone lactylation, forming a feed-forward loop that consolidates the malignant phenotype. Despite advances in therapeutic efforts targeting glycolytic enzymes, challenges remain due to metabolic plasticity, activation of compensatory pathways, and on-target toxicity in normal tissues. Emerging strategies combining glycolytic inhibitors with immunotherapies or microenvironmental modulators have shown promise in preclinical models, but tumor heterogeneity and dynamic metabolic crosstalk still hinder clinical translation. This review synthesizes the mechanistic basis of glycolytic reprogramming, its multifaceted roles in malignancies, and translational barriers that impede therapeutic innovation.

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