LDHA: The Obstacle to T cell responses against tumor

Immunotherapy has become a successful therapeutic strategy in certain solid tumors and hematological malignancies. However, this efficacy of immunotherapy is impeded by limited success rates. Cellular metabolic reprogramming determines the functionality and viability in both cancer cells and immune cells. Extensive research has unraveled that the limited success of immunotherapy is related to immune evasive metabolic reprogramming in tumor cells and immune cells. As an enzyme that catalyzes the final step of glycolysis, lactate dehydrogenase A (LDHA) has become a major focus of research. Here, we have addressed the structure, localization, and biological features of LDHA. Furthermore, we have discussed the various aspects of epigenetic regulation of LDHA expression, such as histone modification, DNA methylation, N6-methyladenosine (m⁶A) RNA methylation, and transcriptional control by noncoding RNA. With a focus on the extrinsic (tumor cells) and intrinsic (T cells) functions of LDHA in T-cell responses against tumors, in this article, we have reviewed the current status of LDHA inhibitors and their combination with T cell-mediated immunotherapies and postulated different strategies for future therapeutic regimens.