The Warburg effect and beyond: Glycolytic reprogramming in cancer progression and emerging therapeutic strategies

Metabolic reprogramming, especially the upretoning and functional reshaping of glycolysis, is the cornerstone of cancer progression, driving proliferation, invasion and metastasis. This review systematically analyzes the Warburg effect. This metabolic transformation promotes the progression of malignant tumors by enhancing glucose uptake, lactate production and microenvironmental remodeling. We elaborated on the molecular basis of this process, focusing on the oncogenic dysregulation of key glycolytic enzymes such as hexokinase 2 (HK2), phosphofructose kinase-1, pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). These malfunctions are usually driven by hyperactive signaling pathways such as PI3K/AKT/mTOR and HIF-1α. This metabolic remodeling also actively shapes the tumor microenvironment (TME) by promoting acidosis, inhibiting anti-tumor immunity and stimulating angiogenesis. Intermediate metabolites in the process of glycolysis can also be used as signal nodes to regulate epithelial-mesenchymal transition (EMT) and maintain the plurity of cancer stem cells (CSC). The cyclic flux of the pentose phosphate pathway (PPP) and the truncated tricarboxylic acid (TCA) cycle flux further highlight the metabolic flexibility inherent in malignant cells. Finally, we critically evaluated emerging treatment strategies for these glycolysis vulnerabilities, including inhibitors of HK2, glucose-6-phosphate dehydrogenase (G6PD), fructose-2,6-diphosphatase3 (PFKFB3) and LDHA. This review reinforces the central position of glycolysis metabolism and emphasizes the potential of tumor treatment.