Mechanistic role of glycolytic pathways in the tumor microenvironment in driving chemoresistance

Abstract

Tumor glycolysis reprogramming, characterized by the “Warburg effect,” has emerged as a critical hallmark of cancer progression and therapeutic resistance. Increasing evidence indicates that enhanced glycolytic activity not only supports rapid tumor growth by sustaining ATP production and biosynthetic demands, but also profoundly contributes to the development of chemoresistance. In resistant tumors, glycolysis-driven metabolic adaptation promotes energy homeostasis, maintains redox balance, enhances DNA damage repair, suppresses apoptosis, and supports cancer stemness, thereby reducing the cytotoxic efficacy of chemotherapeutic agents. Moreover, aberrant glycolytic metabolism extensively remodels the tumor microenvironment (TME) through lactate accumulation, extracellular acidification, hypoxia maintenance, immune suppression, and metabolic crosstalk with stromal cells, collectively facilitating tumor survival and therapeutic tolerance. Importantly, targeting glycolytic pathways has shown promising potential in restoring chemosensitivity and enhancing the efficacy of conventional chemotherapy in multiple malignancies. In this review, we systematically summarize the role of glycolytic reprogramming in maintaining resistant tumor cell metabolic homeostasis, regulating the chemoresistant TME, and driving molecular mechanisms underlying chemotherapy resistance. We further discuss current therapeutic strategies targeting glycolysis and their potential clinical applications for overcoming chemoresistance. A deeper understanding of glycolysis-mediated metabolic plasticity may provide novel insights into precision metabolic intervention and combination therapy in cancer treatment.