Targeting Glycolytic Plasticity to Overcome Therapy Resistance in Cancer Stem Cells: Mechanisms and Clinical Perspectives

Cancer stem cells (CSCs) constitute a resilient tumor subpopulation responsible for multidrug resistance, metastasis, and clinical relapse. A cardinal hallmark of these cells is profound metabolic plasticity. This dynamic defense mechanism facilitates rapid shifts between glycolysis, oxidative phosphorylation (OXPHOS), and alternative nutrient catabolism, enabling CSCs to bypass microenvironmental constraints. This review delineates how glycolytic adaptation functions as a primary driver of therapy resistance within the CSC niche. We dissect the regulatory triad controlling these metabolic shifts, which includes rate-limiting enzymes, epigenetic and epitranscriptomic remodeling, and master transcription factors. Glycolytic reprogramming transcends bioenergetics by acting as a metabolic signaling node. It integrates with the epithelial–mesenchymal transition (EMT) program, autophagic pathways, and the immunosuppressive tumor microenvironment (TME) to fortify CSC survival. We appraise emerging therapeutic interventions targeting these metabolic vulnerabilities. Strategies focus on optimizing small-molecule inhibitors, nanotechnology-enabled delivery systems, and immunometabolic combination regimens. This review establishes a conceptual framework for precision interventions aimed at disrupting CSC plasticity, overcoming therapeutic resistance, and preventing tumor recurrence.