Lactate Metabolism in Cancer: Pathophysiological Mechanisms, and the Modulatory Effects of Exercise

Lactate has traditionally been considered a metabolic byproduct generated during anaerobic glycolysis; however, accumulating evidence demonstrates that it is a key metabolic substrate and signaling molecule involved in cancer progression. Unlike classical hyperlactatemia associated with tissue hypoxia, cancer-related lactate accumulation represents a unique form of Type B hyperlactatemia driven by oncogene-mediated metabolic reprogramming rather than impaired oxygen delivery. The Warburg effect, characterized by preferential aerobic glycolysis despite adequate oxygen availability, enables malignant cells to generate ATP rapidly while simultaneously producing large amounts of lactate. This metabolic adaptation is regulated by signaling pathways including hypoxia-inducible factor-۱α (HIF-۱α), and PI۳K/AKT/mTOR, which increase glucose uptake, glycolytic enzyme activity, and lactate production. Tumor-derived lactate is actively exported through monocarboxylate transporters and accumulates within the tumor microenvironment, where it promotes extracellular acidification, angiogenesis, immune evasion, and metastatic progression. In addition to serving as an energy substrate, lactate functions as a signaling molecule capable of regulating gene expression, thereby linking cellular metabolism with tumor development. Elevated intratumoral lactate concentrations have been associated with poor prognosis, treatment resistance, and reduced overall survival, making lactate an important biomarker and potential therapeutic target. Exercise introduces a physiological contrast to tumor metabolism. Although physical activity transiently increases circulating lactate concentrations, chronic exercise enhances mitochondrial function, oxidative capacity, and systemic lactate clearance. These adaptations reduce dependence on glycolytic metabolism and may disrupt lactate-mediated metabolic symbiosis within tumors. Experimental studies suggest that exercise modifies lactate dehydrogenase isoform expression, improves tumor perfusion, normalizes vascular function, and enhances antitumor immune responses. Consequently, exercise transforms lactate from a tumor-promoting metabolite into a rapidly recycled physiological fuel. This review summarizes the current understanding of lactate metabolism in cancer, highlights its role in tumor biology and clinical outcomes, and discusses the emerging evidence supporting exercise as a metabolic intervention capable of counteracting lactate-dependent mechanisms of cancer progression.

کلیدواژه ها:

Lactate ، Cancer Metabolism ، Warburg Effect ، Exercise ، Tumor Microenvironment