Abstract
Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumour types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The prevalence of the MSI-H/dMMR phenotype is highest in endometrial and colorectal cancers, and this phenotype is associated with a distinct tumour biology, prognosis and responsiveness to various anticancer treatments. In a minority of patients, MSI-H/dMMR cancers result from an inherited pathogenic variant in the context of Lynch syndrome, which has important implications for familial genetic screening. Whether these hereditary cancers have a different biology and clinical behaviour to their sporadic counterparts remains uncertain. Interest in this tumour molecular subtype has increased following the discovery of the high sensitivity of metastatic MSI-H/dMMR cancers to immune-checkpoint inhibitors (ICIs) in a histology-agnostic manner, which reflects the genomic hypermutation resulting from dMMR that renders these tumours highly immunogenic and immune infiltrated. This vulnerability is now also being exploited in early stage disease settings. Despite this common biological foundation, different MSI-H/dMMR cancers have histotype-specific features that correspond to their particular cell or tissue of origin, which might be associated with differences in prognosis and sensitivity to ICIs. In this Review, we provide an overview of the epidemiology, biology, pathogenesis, clinical diagnosis and treatment of MSI-H/dMMR tumours as a histology-agnostic cancer phenomenon. We also highlight peculiarities associated with specific pathogenetic alterations and histologies of MSI-H/dMMR tumours.
Key points
Defects in the DNA mismatch repair machinery lead to the accumulation of organ-specific patterns of mutations and ultimately drive the carcinogenesis of microsatellite instability-high/deficient DNA mismatch repair (MSI-H/dMMR) tumours.
The prevalence of the MSI-H/dMMR phenotype as well as its prognostic and predictive implications, particularly as a biomarker of response to immune-checkpoint inhibitors (ICIs), vary depending on the cancer type.
Universal MSI/MMR testing is pivotal in patients with colorectal, endometrial and gastroesophageal cancers, with active consideration of referral for genetic counselling; immunohistochemistry, PCR and next-generation sequencing assays capture distinct biological features and mechanisms of MSI-H and can provide complementary information.
ICIs have robust efficacy in patients with advanced-stage MSI-H/dMMR cancers, leading to both cancer type-specific and histology-agnostic approvals of anti-PD-1 antibodies; combinations incorporating anti-CTLA4 antibodies might improve outcomes but also increase toxicity.
However, not all MSI-H/dMMR tumours respond to ICIs and — beyond MSI-H/dMMR status — no validated predictive biomarkers for sensitivity of these tumours to ICIs exist; genomic and transcriptomic signatures might have utility in predicting responsiveness and help to refine patient selection, warranting further validation studies.
The implementation of ICIs in the neoadjuvant treatment of early stage MSI-H/dMMR cancers is associated with promising efficacy, potentially enabling non-operative, organ-preservation strategies and improved clinical outcomes.
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Fig. 1: Most common pathogenically mutated genes in MSI-H colorectal, endometrial, gastric and prostate cancers.
Fig. 2: The landscape of the MSI-H/dMMR phenotype across tumour types.
Fig. 3: Timeline of FDA and EMA approvals of ICIs specifically for MSI-H/dMMR cancers.
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Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
Margherita Ambrosini, Paolo Manca, Vincenzo Nasca, Carolina Sciortino, Filippo Ghelardi & Filippo Pietrantonio
Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
Margherita Ambrosini & Julien Taieb
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
Paolo Manca
Division of Oncology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
Jenny F. Seligmann
Paris-Cité University, SIRIC CARPEM Comprehensive Cancer Center, Paris, France
Julien Taieb
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Margherita Ambrosini
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J.F.S. has received honoraria for consultancy and/or advisory roles from Bristol Myers Squibb (BMS), GSK, Johnson & Johnson, Merck Serono, Pierre Fabre, Seagen, Servier and Takeda; speaker’s fees from GSK, Merck Serono, Pierre Fabre, Servier and Takeda; research funding from Amgen, GSK, Pierre Fabre and Merck Serono; travel grants from Takeda; and fees for provision of continuing medical education from GI Connect and OncLive. J.T. has received speaker’s honoraria from Amgen, Astellas, BMS, Merk, Merck Sharp & Dohme (MSD) and Novartis; has participated on advisory boards for Amgen, BMS, Merck, MSD, Novartis, Pfizer, Pierre Fabre, Rottapharm, Sanofi, Servier and Takeda; has provided expert testimony for Takeda; and has participated on steering committees of clinical trial for Novartis. F.P. has received institutional research funding from Agenus, Amgen, AstraZeneca, BMS, Incyte, Lilly and Rottapharm; speaker’s honoraria from Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi-Sankyo, Ipsen, Johnson & Johnson, Merck Serono, MSD, Pierre Fabre, Seagen, Servier and Takeda; fees for advisory or consultancy roles from Agenus, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi-Sankyo, Gilead, GSK, Italfarmaco, Incyte, Jazz Pharmaceuticals, Johnson & Johnson, Merck-Serono, MSD, Pfizer, Pierre Fabre, Rottapharm, Servier and Takeda. The other authors declare no competing interests.
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Ambrosini, M., Manca, P., Nasca, V. et al. Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers. Nat Rev Clin Oncol (2025). https://doi.org/10.1038/s41571-025-01015-z
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DOI:https://doi.org/10.1038/s41571-025-01015-z
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