The regulatory roles of dysregulated lactate dehydrogenase A in anti-tumor immunity within immune cells

Malignant tumors maintain proliferative, invasive, and metastatic capacities through metabolic reprogramming. Lactate dehydrogenase A (LDHA), is an essential glycolytic enzyme that is aberrantly overexpressed in diverse human malignancies. The enzymatic activity of LDHA is tightly modulated by multiple post-translational modifications, including acetylation, phosphorylation, and lactylation. LDHA promotes the Warburg effect and lactate accumulation, while participating in tumor DNA damage repair, malignant progression, and drug resistance. LDHA and its metabolite lactate substantially modulate the differentiation and functional status of tumor-infiltrating immune cells, including lymphoid and myeloid cells. These metabolic changes remodel the tumor immune microenvironment and regulate anti-tumor immune responses in a context-dependent manner. This review systematically summarizes the regulatory mechanisms of LDHA in immune cell metabolism and anti-tumor immunity. Additionally, it discusses the clinical potential of LDHA as a promising anti-tumor therapeutic target and explores the application prospects of combining LDHA inhibitors with immunotherapies, such as chimeric antigen receptor T-cell (CAR-T) therapy and immune checkpoint blockade. This study aims to provide novel perspectives for the research and development of tumor targeted therapies.