Defective DNA mismatch repair (dMMR) means the cell’s normal “proofreading” system for fixing base–base mismatches and small insertion/deletion errors during DNA replication is not working properly. When the MMR pathway is intact, it recognizes mismatches, excises a stretch of the newly synthesized strand containing the error, and resynthesizes it correctly, increasing replication fidelity by 100–1000‑fold.
In humans, this system is mainly mediated by MMR proteins encoded by MLH1, MSH2, MSH6, PMS2, and related partners; loss of function (germline or somatic) in these genes leads to dMMR. Functionally, dMMR cells fail to correct replication errors, especially in repetitive (microsatellite) regions, causing accumulation of base substitutions and insertion/deletion loops and resulting in microsatellite instability (MSI‑high) and a high mutational burden.
Clinically, dMMR is detected either by immunohistochemistry showing loss of one or more MMR proteins or indirectly via molecular demonstration of MSI‑high status (PCR or NGS‑based assays). dMMR underlies Lynch syndrome and a subset of sporadic tumors and is a key predictive biomarker for response to immune checkpoint inhibitors because the high neoantigen load makes these tumors more immunogenic