LDH‐A negatively regulates dMMR in colorectal cancer

Although immune checkpoint inhibitors (ICIs) have achieved unprecedented success in dMMR tumors, pMMR tumors accounting for 85% of colorectal cancer (CRC) cases remain unresponsive. Lactate dehydrogenase A (LDH‐A) is the rate‐limiting enzyme that catalyzes the transformation of pyruvate to lactate in the process of glycolysis. We investigated the relationship between LDH‐A and dMMR with the purpose of exploring the treatment strategy for pMMR CRC patients. We here show that LDH‐A can promote the proliferation of dMMR and pMMR CRC cells by positively regulating MMR proteins both in vitro and in vivo. LDH‐A inhibition can improve the efficacy of PD‐1 blockade in a pMMR CRC xenograft model. A statistical analysis of 186 CRC specimens showed a significant correlation between LDH‐A and dMMR status. Moreover, patients with both low LDH‐A expression and dMMR exhibited better disease‐free survival compared with patients with other combinations. The close correlation of LDH‐A and dMMR may offer a promising therapeutic strategy in which the combination of LDH‐A inhibitor and ICIs may improve the clinical benefit for pMMR CRC patients.