Rewiring Glycolysis in Cancer: From Tumor Initiation to Therapeutic Vulnerabilities

Glycolysis is a defining feature of cancer metabolism, originally described by the Warburg effect. Increasing evidence indicates that cancer-associated glycolysis is not uniformly upregulated but dynamically rewired in response to oncogenic signaling, cellular demands, and microenvironmental cues. However, a framework integrating its temporal evolution and functional roles across tumorigenesis remains limited. In particular, how glycolytic rewiring drives malignant transformation, adapts during tumor progression, and generates context-dependent vulnerabilities has not been systematically synthesized. In this review, we examine glycolysis as a dynamic metabolic network evolving throughout tumor development. We discuss how early glycolytic rewiring, driven by oncogenic signaling and metabolic–epigenetic coupling, supports cell fate transitions and establishes redox and biosynthetic capacity during tumorigenesis. We then outline how glycolysis is remodeled during tumor progression through coordinated transcriptional, epigenetic, and post-translational regulation, as well as microenvironmental interactions and metabolic heterogeneity. Furthermore, we highlight glycolysis as an integrative hub linking immune evasion, cell death regulation, and metabolic plasticity, and discuss how glycolytic rewiring creates context-dependent metabolic dependencies that may be therapeutically exploited, along with emerging technologies that enable high-resolution characterization of tumor metabolism. Together, this review provides a conceptual framework for understanding glycolytic rewiring in cancer and outlines potential avenues for targeting metabolic vulnerabilities.