Abstract
DNA mismatch repair (MMR) preserves genomic integrity by correcting replication errors. Deficiency in MMR results in microsatellite instability, increased tumor mutational burden, neoantigen generation, and activation of the immune response. In this review, we first outline how MMR loss promotes immune activation and responsiveness to immune checkpoint blockade (ICB), establishing MMR-deficient (MMRd) status as the first tumor-agnostic biomarker for ICB therapy. Subsequently, we summarize 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 discuss the implications of the 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 immune-cold cancers. We then explore strategies to exploit MMR dynamics and mimic MMRd-like phenotypes through alkylating agents, pharmacologic MMR inhibition, and stress-mediated modulation, with the aim of sensitizing refractory tumors to immunotherapy. Finally, we report 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.