Mismatch Repair as a Dynamic and Clinically Actionable Vulnerability in Cancer

Abstract DNA mismatch repair (MMR) preserves genomic integrity by correcting replication errors. Deficiency in MMR (MMRd) results in microsatellite instability, increased tumor mutational burden, neoantigen generation, and activation of immune response. In this review, we first outlined how MMR loss promotes immune activation and responsiveness to immune checkpoint blockade (ICB), establishing MMRd status as the first tumor-agnostic biomarker for ICB therapy. Subsequently, we summarized the compelling evidence that defines MMR status as a dynamic, context-dependent process influenced by environmental and therapeutic pressures, rather than a fixed, binary trait. Accordingly, we discussed the implications of spatial and temporal heterogeneity of MMR status for both the diagnosis and treatment of cancer, the differential response of MMRd tumors to ICB, as well as the occasional benefits observed in MMR-proficient (MMRp) immune-cold cancers. We then explored strategies to exploit MMR dynamics and mimic MMRd-like phenotypes through alkylating agents, pharmacological MMR inhibition, and stress-mediated modulation, with the aim of sensitizing refractory tumors to immunotherapy. Finally, we reported emerging therapeutic opportunities in MMRd tumors, including Werner helicase inhibition, nonsense-mediated decay blockade, and neoantigen-targeted vaccines. Altogether, reframing MMR as a dynamic and targetable axis may broaden immunotherapy applicability and advance precision immune oncology across different tumor types.