In recent years, the intricate relationship between DNA repair mechanisms and cancer development has come into sharper focus, spotlighting a molecular phenomenon that transcends traditional cancer classifications. Deficiency in DNA mismatch repair (dMMR) represents one of the most compelling pathways to carcinogenesis, underpinning a distinct molecular signature characterized by microsatellite instability-high (MSI-H) status. This defect, observed across an array of tumor types, fundamentally alters the genomic landscape of cancer cells, instigating cascading changes in tumor biology, patient prognosis, and therapeutic responsiveness. It is this universality—and the intriguing complexities within—that has galvanized researchers to delve deeper into MSI-H/dMMR cancers, revealing critical insights that could reshape oncology paradigms.
The prevalence of MSI-H/dMMR phenotypes is particularly pronounced in endometrial and colorectal malignancies, where they serve not just as molecular hallmarks but as markers intertwined with unique biological behaviors and clinical outcomes. These tumors, distinguished by their hypermutated genomic profiles, demonstrate a marked sensitivity to emerging anticancer therapies, notably immune-checkpoint inhibitors (ICIs). This therapeutic vulnerability arises from the tumors’ hypermutated state, a direct consequence of defective mismatch repair, which creates a permissive environment for increased neoantigen presentation. Such immunogenicity invites robust infiltration by immune cells, setting the stage for effective immunomodulatory interventions.
A nuanced dimension of MSI-H/dMMR cancers is introduced through the lens of hereditary cancer syndromes, predominantly Lynch syndrome. This autosomal dominant inherited condition results from germline pathogenic variants in mismatch repair genes, predisposing carriers to a spectrum of malignancies manifesting the MSI-H/dMMR phenotype. While the majority of MSI-H/dMMR cancers are sporadic, the subset arising from Lynch syndrome carries significant implications not only for personalized treatment strategies but also for familial genetic counseling and cancer risk assessment. Yet, the exact distinctions, if any, in molecular pathogenesis and clinical behavior between hereditary and sporadic MSI-H/dMMR tumors remain a subject of ongoing investigation, underscoring a critical knowledge gap.
The expanding interest in MSI-H/dMMR tumors has been propelled further by the remarkable clinical responses observed with ICIs in metastatic disease across diverse histologies. This histology-agnostic efficacy exemplifies precision oncology’s promise: targeting molecular vulnerabilities irrespective of the cancer’s tissue of origin. The mechanistic basis lies in the hypermutation driven by mismatch repair deficiency which produces a myriad of neoepitopes recognizable by the immune system. This intrinsic immunogenicity not only renders these cancers responsive to immune checkpoint blockade but also fuels optimism for expanding immunotherapies into adjuvant and neoadjuvant settings, potentially transforming management paradigms for early-stage MSI-H/dMMR malignancies.
Despite the shared molecular underpinning of MSI-H/dMMR status, tumors arising from different tissues exhibit distinct histopathological and biological features. These tissue-specific characteristics influence not only prognosis but also the degree of responsiveness to immune-based therapies. For example, MSI-H colorectal cancers often present with marked lymphocytic infiltration, whereas MSI-H endometrial cancers may display divergent tumor microenvironments influencing immunotherapy outcomes. Such variability underscores the necessity of integrating molecular profiling with histotype-specific contexts when devising treatment regimens, advocating for a precision medicine approach that respects both shared and unique tumor biology.
At a molecular level, mismatch repair involves a highly orchestrated proofreading system tasked with identifying and rectifying base-base mismatches and insertion-deletion loops during DNA replication. Key proteins such as MLH1, MSH2, MSH6, and PMS2 coordinate this repair cascade, preserving genomic integrity. Loss of function in any of these components through somatic mutations, epigenetic silencing—especially MLH1 promoter hypermethylation—or germline alterations impairs DNA repair fidelity. The resulting accumulation of mutations fosters microsatellite instability characterized by length alterations in repetitive DNA sequences scattered throughout the genome, a hallmark detected by specific diagnostic assays.
Clinically, MSI-H/dMMR status has become an indispensable biomarker for guiding therapeutic decision-making. Historically, its prognostic value varied by tumor type; for instance, MSI-H colorectal cancers often confer favorable prognosis compared to microsatellite stable counterparts. However, the advent of immunotherapy has shifted MSI-H/dMMR status to the forefront as a predictive biomarker for ICI responsiveness. Regulatory approvals now endorse MSI-H/dMMR testing as a standard component of diagnostic workflows for colorectal, endometrial, and other relevant cancers, reflecting a paradigm shift towards biomarker-driven oncology.
Diagnostic modalities include both molecular assays and immunohistochemical (IHC) staining to evaluate mismatch repair protein expression and assess microsatellite instability. Polymerase chain reaction (PCR)-based panels targeting mononucleotide and dinucleotide repeats remain gold standards for MSI detection, while IHC offers a practical approach to evaluate MLH1, MSH2, MSH6, and PMS2 protein presence within tumor samples. Concordance between these methods is generally high, yet discordances may arise, necessitating comprehensive evaluation especially in the context of clinical trial enrollment and treatment planning.
The therapeutic landscape for MSI-H/dMMR cancers is rapidly evolving. Immune-checkpoint blockade targeting programmed cell death protein 1 (PD-1) and its ligand (PD-L1), as well as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), have demonstrated unprecedented efficacy. Clinical trials established durable responses and improved survival in metastatic MSI-H/dMMR colorectal and non-colorectal cancers, leading to histology-agnostic approvals by regulatory agencies. This success has spurred exploration of combinatorial regimens, immunotherapy in earlier disease stages, and the identification of biomarkers beyond MSI-H/dMMR to predict treatment response.
However, challenges remain. Not all MSI-H/dMMR tumors respond uniformly to immunotherapy, highlighting intrinsic resistance mechanisms and the influence of tumor microenvironmental factors. Variability in tumor-infiltrating lymphocyte density, expression of alternative immune checkpoints, and presence of immunosuppressive cells such as myeloid-derived suppressor cells may modulate therapeutic efficacy. Future research is prioritizing elucidation of these resistance pathways to optimize patient selection and develop next-generation immunotherapies.
Beyond immune checkpoint inhibitors, understanding the biology of MSI-H/dMMR tumors opens avenues for novel treatments targeting DNA repair deficiencies directly. Agents inducing synthetic lethality via interaction with other DNA damage response pathways, or epigenetic modulators reversing MLH1 promoter methylation, represent areas of active investigation. Integration of these strategies may potentiate immunotherapy effectiveness or provide alternatives for patients who are refractory to current standards.
Furthermore, the intersection of MSI-H/dMMR status with tumor genomics has unveiled complex pathogenetic landscapes. Co-occurring mutations in oncogenes and tumor suppressors, tumor mutational burden variability, and neoantigen heterogeneity contribute to clinical behavior and therapeutic responses. Advanced sequencing technologies and bioinformatics have become indispensable in dissecting these layers, enabling refined stratification and personalized treatment approaches.
The implications of MSI-H/dMMR extend beyond oncology clinics into public health domains. Identification of Lynch syndrome carriers through tumor testing facilitates cascade genetic screening in families, providing opportunities for cancer prevention and early detection. This necessitates coordinated multidisciplinary efforts encompassing molecular diagnostics, genetic counseling, and surveillance protocols, underscoring the societal impact of understanding MSI-H/dMMR biology.
In summary, the landscape of MSI-H/dMMR cancers reflects a remarkable convergence of molecular biology, clinical oncology, and immunotherapy innovation. From fundamental insights into DNA repair dysfunction to transformative immunotherapeutic successes, this tumor subtype exemplifies the potential of precision oncology approaches. Continued research to unravel tissue-specific nuances, resistance mechanisms, and novel therapeutic targets promises to refine patient management strategies further, heralding a new era where histology-agnostic molecular profiling guides individualized cancer care.
The burgeoning recognition of MSI-H/dMMR tumors’ complex biology and their role in shaping immune response underscores the necessity for comprehensive, multidisciplinary research and clinical integration. As the scientific community advances toward expanding therapeutic indications and refining diagnostic tools, patients with MSI-H/dMMR cancers stand at the forefront of benefit from personalized medicine breakthroughs. This evolving paradigm not only redefines treatment but also enriches understanding of carcinogenesis itself, providing hope for improved outcomes across cancer types.
Subject of Research: DNA mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) cancers including epidemiology, biology, pathogenesis, diagnosis, and treatment, with emphasis on immunotherapy and hereditary syndromes such as Lynch syndrome.
Article Title: Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.
Article References:
Ambrosini, M., Manca, P., Nasca, V. et al. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.
Nat Rev Clin Oncol 22, 385–407 (2025). https://doi.org/10.1038/s41571-025-01015-z
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