Mismatch Repair Deficiency and the Role of Non-Canonical Functions in Cancer: Diagnosis and Therapeutic Implications

The mismatch repair system is critical for correcting base–base mismatches and insertion-deletion loops during DNA replication. Deficiencies in MMR (due to mutations in MLH1, MSH2, MSH6, or PMS2) lead to microsatellite instability and contribute to the development of various cancers, such as Lynch syndrome-related colorectal cancer and sporadic tumors. This review will delve into the molecular basis of MMR deficiency. Additionally, the review will cover diagnostic approaches for detecting MSI and MMR deficiency, including next-generation sequencing and PCR-based methods. The implications for treatment will be discussed, emphasizing immune checkpoint inhibitors (e.g., pembrolizumab) that target tumors with high mutational burdens due to MMR deficiency, as well as novel therapeutic approaches like synthetic lethality exploiting DNA repair vulnerabilities.