LDHA-mediated metabolic reprogramming: a key driver of tumor malignancy

Metabolic reprogramming is one of the core hallmarks of malignant tumors, among which the abnormally enhanced glycolysis driven by the Warburg effect constitutes a critical aspect of tumor metabolic remodeling. LDHA is abnormally highly expressed in various tumors, and its expression level is closely related to tumor malignancy. The high expression of LDHA is not limited to overall elevation but also exhibits spatial heterogeneity. LDHA expression is significantly higher in highly invasive tumor edge regions compared to low-invasive regions. LDHA maintains high glycolytic flux by catalyzing the conversion of pyruvate to lactate while regenerating NAD + , rapidly producing ATP to meet the energy demands of rapid tumor cell proliferation. Lactate produced through high glycolytic flux can be taken up by cancer-associated fibroblasts (CAFs) via MCT1 and enter the tricarboxylic acid cycle, promoting CAF proliferation. LDHA expression levels are positively and significantly correlated with intracellular lactate concentrations, and lactate, as the direct substrate source for histone lactylation modifications, changes in its abundance directly regulate histone lactylation levels. Lactate acts as an alternative energy substrate, providing fuel for oxidative tumor cells or tumor-associated stromal cells via monocarboxylate transporter (MCT1/4)-mediated lactate shuttle, forming a metabolic symbiosis network. The acidification of the tumor microenvironment, directly inhibiting T cell function, promoting T cell differentiation toward regulatory T cells, upregulating the expression of inhibitory receptors on the T cell surface to induce T cell exhaustion, and interfering with the formation of memory T cells. It also promotes macrophage polarization from the pro-inflammatory M1 type to the immunosuppressive M2 type, enhancing their tumor-promoting growth, angiogenesis, and tissue remodeling functions. Currently, LDHA inhibitors (e.g., FX-11 and GSK2837808A) and MCT1 inhibitors (e.g., AZD3965) have shown preclinical potential in suppressing tumor growth, reversing immunosuppression, and sensitizing conventional therapies. Some of these agents have already advanced into early-stage clinical trials. However, this strategy still faces challenges including enhanced tumor metabolic plasticity, on-target toxicity, and a lack of predictive biomarkers. Future research should focus on optimizing combination therapy strategies, elucidating mechanisms of metabolic adaptation, and enabling precise patient selection, thereby advancing novel therapeutic approaches based on lactate metabolism intervention toward clinical translation.