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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
27,99 € / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
209,00 € per year
only 17,42 € per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Warren, J. J. et al. Structure of the human MutSalpha DNA lesion recognition complex. Mol. Cell 26, 579–592 (2007).
Park, J. C. et al. MutSα and MutSβ as size-dependent cellular determinants for prime editing in human embryonic stem cells. Mol. Ther. Nucleic Acids 32, 914–922 (2023).
Longley, M. J., Pierce, A. J. & Modrich, P. DNA polymerase δ is required for human mismatch repair in vitro. J. Biol. Chem. 272, 10917–10921 (1997).
Bradford, K. C. et al. Dynamic human MutSα–MutLα complexes compact mismatched DNA. Proc. Natl Acad. Sci. USA 117, 16302–16312 (2020).
Sammalkorpi, H. et al. Background mutation frequency in microsatellite-unstable colorectal cancer. Cancer Res. 67, 5691–5698 (2007).
Kim, T. M., Laird, P. W. & Park, P. J. The landscape of microsatellite instability in colorectal and endometrial cancer genomes. Cell 155, 858 (2013).
Laiho, P. et al. Low-level microsatellite instability in most colorectal carcinomas. Cancer Res. 62, 1166–1170 (2002).
Umar, A. et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J. Natl Cancer Inst. 96, 261–268 (2004).
Ligtenberg, M. J. L., Kuiper, R. P., Geurts Van Kessel, A. & Hoogerbrugge, N. EPCAM deletion carriers constitute a unique subgroup of Lynch syndrome patients. Fam. Cancer 12, 169–174 (2013).
Lee, B. C. H. et al. Mutational landscape of normal epithelial cells in Lynch syndrome patients. Nat. Commun. 13, 1–10 (2022).
Veigl, M. L. et al. Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. Proc. Natl Acad. Sci. USA 95, 8698–8702 (1998).
Mensenkamp, A. R. et al. Somatic mutations in MLH1 and MSH2 are a frequent cause of mismatch-repair deficiency in Lynch syndrome-like tumors. Gastroenterology 146, 643–646.e8 (2014).
Picó, M. D. et al. Clinical and pathological characterization of Lynch-like syndrome. Clin. Gastroenterol. Hepatol. 18, 368–374.e1 (2020).
Rodríguez-Soler, M. et al. Risk of cancer in cases of suspected Lynch syndrome without germline mutation. Gastroenterology 144, 926–932.e1 (2013).
Salem, M. E. et al. Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors. Int. J. Cancer 147, 2948–2956 (2020).
Jaffrelot, M. et al. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod. Pathol. 35, 427–437 (2022).
Ahadova, A. et al. Three molecular pathways model colorectal carcinogenesis in Lynch syndrome. Int. J. Cancer 143, 139–150 (2018).
Ahadova, A., von Knebel Doeberitz, M., Bläker, H. & Kloor, M. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam. Cancer 15, 579–586 (2016).
Weisenberger, D. J. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 38, 787–793 (2006).
Yozu, M. et al. Loss of expression of MLH1 in non-dysplastic crypts is a harbinger of neoplastic progression in sessile serrated adenomas/polyps. Histopathology 75, 376–384 (2019).
De Palma, F. D. E. et al. The molecular hallmarks of the serrated pathway in colorectal cancer. Cancers 11, 1017 (2019).
Roudko, V. et al. Shared immunogenic poly-epitope frameshift mutations in microsatellite unstable tumors. Cell 183, 1634–1649.e17 (2020).
Bass, A. J. et al. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513, 202–209 (2014).
Getz, G. et al. Integrated genomic characterization of endometrial carcinoma. Nature 497, 67–73 (2013).
Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).
Ferreira, A. M. et al. New target genes in endometrial tumors show a role for the estrogen-receptor pathway in microsatellite-unstable cancers. Hum. Mutat. 35, 1514–1523 (2014).
Ma, Y. T. et al. Clinicopathological characteristics, molecular landscape, and biomarker landscape for predicting the efficacy of PD-1/PD-L1 inhibitors in Chinese population with mismatch repair deficient urothelial carcinoma: a real-world study. Front. Immunol. 14, 1269097 (2023).
Zhang, H. et al. Clinicopathological and molecular analysis of microsatellite instability in prostate cancer: a multi-institutional study in China. Front. Oncol. 13, 1277233 (2023).
Schweizer, M. T. et al. Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations. JCO Precis. Oncol. 3, 1–9 (2019).
Luksza, M. et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature 551, 517–520 (2017).
Bauer, K. et al. T cell responses against microsatellite instability-induced frameshift peptides and influence of regulatory T cells in colorectal cancer. Cancer Immunol. Immunother. 62, 27–37 (2013).
Llosa, N. J. et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43–51 (2015).
Grasso, C. S. et al. Genetic mechanisms of immune evasion in colorectal cancer. Cancer Discov. 8, 730–749 (2018).
Kloor, M. et al. β2-microglobulin mutations in microsatellite unstable colorectal tumors. Int. J. Cancer 121, 454–458 (2007).
Michel, S. et al. Lack of HLA class II antigen expression in microsatellite unstable colorectal carcinomas is caused by mutations in HLA class II regulatory genes. Int. J. Cancer 127, 889–898 (2010).
Albacker, L. A. et al. Loss of function JAK1 mutations occur at high frequency in cancers with microsatellite instability and are suggestive of immune evasion. PLoS ONE 12, e0176181 (2017).
Liu, G. C. et al. The heterogeneity between Lynch-associated and sporadic MMR deficiency in colorectal cancers. J. Natl Cancer Inst. 110, 975–984 (2018).
Ramchander, N. C. et al. Distinct immunological landscapes characterize inherited and sporadic mismatch repair deficient endometrial cancer. Front. Immunol. 10, 503158 (2020).
Chow, R. D. et al. Distinct mechanisms of mismatch-repair deficiency delineate two modes of response to anti–PD-1 immunotherapy in endometrial carcinoma. Cancer Discov. 13, 312–331 (2023).
Bellone, S. et al. A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability. Cancer 128, 1206–1218 (2022).
Bonneville, R. et al. Landscape of microsatellite instability across 39 cancer types. JCO Precis. Oncol. 2017, 1–15 (2017).
Latham, A. et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J. Clin. Oncol. 37, 286–295 (2018).
Hause, R. J., Pritchard, C. C., Shendure, J. & Salipante, S. J. Classification and characterization of microsatellite instability across 18 cancer types. Nat. Med. 22, 1342–1350 (2016).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
Cortes-Ciriano, I., Lee, S., Park, W.-Y., Kim, T.-M. & Park, P. J. A molecular portrait of microsatellite instability across multiple cancers. Nat. Commun. 8, 15180 (2017).
Power, R. F. et al. Modifiable risk factors and risk of colorectal and endometrial cancers in Lynch syndrome: a systematic review and meta-analysis. JCO Precis. Oncol. 8, e2300196 (2024).
Carr, P. R. et al. Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses. Ann. Oncol. 29, 825–834 (2018).
Wang, X. et al. Association between smoking and molecular subtypes of colorectal cancer. JNCI Cancer Spectr. 5, pkab056 (2021).
Amankwah, E. K. et al. Hormonal and reproductive risk factors for sporadic microsatellite stable and unstable endometrial tumors. Cancer Epidemiol. Biomark. Prev. 22, 1325–1331 (2013).
Roth, A. D. et al. Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. J. Natl Cancer Inst. 104, 1635–1646 (2012).
Sinicrope, F. A. et al. DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J. Natl Cancer Inst. 103, 863–875 (2011).
Hutchins, G. et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer. J. Clin. Oncol. 29, 1261–1270 (2011).
Sargent, D. J. et al. Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J. Clin. Oncol. 28, 3219–3226 (2010).
Meyers, M., Wagner, M. W., Hwang, H.-S., Kinsella, T. J. & Boothman, D. A. Role of the HMLH1 DNA mismatch repair protein in fluoropyrimidine-mediated cell death and cell cycle responses 1. Cancer Res. 61, 5193–5201 (2001).
Argilés, G. et al. Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 31, 1291–1305 (2020).
Benson, A. B. et al. NCCN Guidelines Version 1.2025 Colon Cancer (NCCN, 2025).
Cohen, R. et al. Microsatellite instability in patients with stage iii colon cancer receiving fluoropyrimidine with or without oxaliplatin: an ACCENT pooled analysis of 12 adjuvant trials. J. Clin. Oncol. 39, 642–651 (2021).
Morton, D. et al. Preoperative chemotherapy for operable colon cancer: mature results of an international randomized controlled trial. J. Clin. Oncol. 41, 1541–1552 (2023).
Hu, H. et al. Neoadjuvant chemotherapy with oxaliplatin and fluoropyrimidine versus upfront surgery for locally advanced colon cancer: the randomized, phase III OPTICAL trial. J. Clin. Oncol. https://doi.org/10.1200/JCO.23.01889 (2024).
Chalabi, M. et al. Neoadjuvant immunotherapy in locally advanced mismatch repair–deficient colon cancer. N. Engl. J. Med. 390, 1949–1958 (2024).
Smyth, E. C. et al. Mismatch repair deficiency, microsatellite instability, and survival: an exploratory analysis of the medical research council adjuvant gastric infusional chemotherapy (MAGIC) trial. JAMA Oncol. 3, 1197–1203 (2017).
Pietrantonio, F. et al. Individual patient data meta-analysis of the value of microsatellite instability as a biomarker in gastric cancer. J. Clin. Oncol. 37, 3392–3400 (2019).
Lordick, F. et al. Gastric cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 1005–1020 (2022).
Lordick, F. et al. ESMO Gastric Cancer Living Guideline, v1.4 September 2024 https://www.esmo.org/living-guidelines/esmo-gastric-cancer-living-guideline (ESMO, 2024).
Al-Batran, S. E. et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 393, 1948–1957 (2019).
André, T. et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: the GERCOR NEONIPIGA phase II study. J. Clin. Oncol. 41, 255–265 (2023).
Lorenzen, S. et al. Perioperative atezolizumab plus fluorouracil, leucovorin, oxaliplatin, and docetaxel for resectable esophagogastric cancer: interim results from the randomized, multicenter, phase II/III DANTE/IKF-s633 trial. J. Clin. Oncol. 42, 410–420 (2024).
Shitara, K. et al. Neoadjuvant and adjuvant pembrolizumab plus chemotherapy in locally advanced gastric or gastro-oesophageal cancer (KEYNOTE-585): an interim analysis of the multicentre, double-blind, randomised phase 3 study. Lancet Oncol. 25, 212–224 (2024).
Janjigian, Y. Y. et al. LBA73 Pathological complete response (pCR) to durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric and gastroesophageal junction cancer (GC/GEJC): Interim results of the global, phase III MATTERHORN study. Ann. Oncol. 34, S1315–S1316 (2023).
Raimondi, A. et al. Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO. Ann. Oncol. 36, 285–296 (2025).
Ajani, J. A. & D’Amico, T. A. NCCN Guidelines Version 5.2024 Gastric Cancer (NCCN, 2024).
Janjigian, Y. Y. et al. Genetic predictors of response to systemic therapy in esophagogastric cancer. Cancer Discov. 8, 49–58 (2018).
Venderbosch, S. et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin. Cancer Res. 20, 5322–5330 (2014).
André, T. et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N. Engl. J. Med. 383, 2207–2218 (2020).
Chao, J. et al. Assessment of pembrolizumab therapy for the treatment of microsatellite instability-high gastric or gastroesophageal junction cancer among patients in the KEYNOTE-059, KEYNOTE-061, and KEYNOTE-062 clinical trials. JAMA Oncol. 7, 895–902 (2021).
Ludford, K. et al. Pathological tumor response following immune checkpoint blockade for deficient mismatch repair advanced colorectal cancer. J. Natl Cancer Inst. 113, 208–211 (2021).
Oaknin, A. et al. Endometrial cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann. Oncol. 33, 860–877 (2022).
Concin, N. et al. ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma. Int. J. Gynecol. Cancer 31, 12–39 (2021).
Lé On-Castillo, A. et al. Molecular classification of the PORTEC-3 trial for high-risk endometrial cancer: impact on prognosis and benefit from adjuvant therapy. J. Clin. Oncol. 38, 3388–3397 (2020).
Horeweg, N. et al. Molecular classification predicts response to radiotherapy in the randomized PORTEC-1 and PORTEC-2 trials for early-stage endometrioid endometrial cancer. J. Clin. Oncol. https://doi.org/10.1200/JCO.23.00062 (2017).
Van Den Heerik, A. S. V. M. et al. PORTEC-4a: international randomized trial of molecular profile-based adjuvant treatment for women with high-intermediate risk endometrial cancer. Int. J. Gynecol. Cancer 30, 2002–2007 (2020).
Van Gorp, T. et al. ENGOT-en11/GOG-3053/KEYNOTE-B21: a randomised, double-blind, phase III study of pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy in patients with newly diagnosed, high-risk endometrial cancer 5 behalf of the ENGOT-en11/GOG-3053/KEYNOTE-B21 investigators. Ann. Oncol. 35, 968–980 (2024).
Liu, Y. et al. Comparative molecular analysis of gastrointestinal adenocarcinomas. Cancer Cell 33, 721–735.e8 (2018).
Halvarsson, B., Anderson, H., Domanska, K., Lindmark, G. & Nilhert, M. Clinicopathologic factors identify sporadic mismatch repair-defective colon cancers. Am. J. Clin. Pathol. 129, 238–244 (2008).
Nakagawa, H. et al. Age-related hypermethylation of the 5 region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development 1. Cancer Res. http://aacrjournals.org/cancerres/article-pdf/61/19/6991/2487214/ch1901006991.pdf (2001).
Polom, K. et al. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br. J. Surg. 105, 159–167 (2018).
Latham, A. et al. Characterization and clinical outcomes of DNA mismatch repair-deficient small bowel adenocarcinoma. Clin. Cancer Res. 27, 1429–1437 (2021).
Manning-Geist, B. L. et al. Microsatellite instability-high endometrial cancers with MLH1 promoter hypermethylation have distinct molecular and clinical profiles. Clin. Cancer Res. 28, 4302–4311 (2022).
Chandran, E. B. A. et al. Mismatch repair deficiency and microsatellite instability in urothelial carcinoma: a systematic review and meta-analysis. BMJ Oncol. 3, 335 (2024).
Vasen, H. F. A., Watson, P., Mecklin, J. P. & Lynch, H. T. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116, 1453–1456 (1999).
Kastrinos, F., Balmaña, J. & Syngal, S. Prediction models in Lynch syndrome. Fam. Cancer 12, 217–228 (2013).
Stjepanovic, N. et al. Hereditary gastrointestinal cancers: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Ann. Oncol. 30, 1558–1571 (2019).
National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric - Guidelines Detail https://www.nccn.org/guidelines/guidelines-detail?category=2&id=1544 (NCCN, 2024).
Adar, T. et al. A tailored approach to BRAF and MLH1 methylation testing in a universal screening program for Lynch syndrome. Mod. Pathol. 30, 440–447 (2017).
Gayhart, M. G. et al. Universal mismatch repair protein screening in upper tract urothelial carcinoma: a validation study with comparison to colorectal and endometrial adenocarcinoma. Am. J. Clin. Pathol. 154, 792–801 (2020).
Food and Drug Administration. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-advanced-solid-tumors (2023).
Food and Drug Administration. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication (2017).
Dedeurwaerdere, F. et al. Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer. Sci. Rep. 11, 12880 (2021).
Gilson, P. et al. Evaluation of 3 molecular-based assays for microsatellite instability detection in formalin-fixed tissues of patients with endometrial and colorectal cancers. Sci. Rep. 10, 1–10 (2020).
Hechtman, J. F. et al. Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes. Mod. Pathol. 33, 871–879 (2020).
Luchini, C. et al. ESMO recommendations on microsatellite instability testing for immunotherapy in cancer, and its relationship with PD-1/PD-L1 expression and tumour mutational burden: a systematic review-based approach. Ann. Oncol. 30, 1232–1243 (2019).
Vikas, P. et al. Mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy: ASCO endorsement of college of American Pathologists Guideline. J. Clin. Oncol. 41, 1943–1948 (2023).
Pearlman, R. et al. Two-stain immunohistochemical screening for Lynch syndrome in colorectal cancer may fail to detect mismatch repair deficiency. Mod. Pathol. 31, 1891–1900 (2018).
Parente, P. et al. The day-to-day practice of MMR and MSI assessment in colorectal adenocarcinoma: what we know and what we still need to explore. Digestive Dis. 41, 746–756 (2023).
Verma, L. et al. Mononucleotide microsatellite instability and germline MSH6 mutation analysis in early onset colorectal cancer. J. Med. Genet. 36, 678 (1999).
Buhard, O. et al. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J. Clin. Oncol. 24, 241–251 (2006).
Wang, Y., Shi, C., Eisenberg, R. & Vnencak-Jones, C. L. Differences in microsatellite instability profiles between endometrioid and colorectal cancers: a potential cause for false-negative results? J. Mol. Diagnostics 19, 57–64 (2017).
Chung, Y. et al. Evaluation of an eight marker-panel including long mononucleotide repeat markers to detect microsatellite instability in colorectal, gastric, and endometrial cancers. BMC Cancer 23, 1–11 (2023).
Hampel, H. et al. Assessment of tumor sequencing as a replacement for Lynch syndrome screening and current molecular tests for patients with colorectal cancer. JAMA Oncol. 4, 806–813 (2018).
Kather, J. N. et al. Deep learning can predict microsatellite instability directly from histology in gastrointestinal cancer. Nat. Med. 25, 1054–1056 (2019).
Gustav, M. et al. Deep learning for dual detection of microsatellite instability and POLE mutations in colorectal cancer histopathology. npj Precis. Oncol. 8, 115 (2024).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Le, D. T. et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J. Clin. Oncol. 38, 11–19 (2019).
O’Malley, D. M. et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. J. Clin. Oncol. 40, 752–761 (2022).
Oaknin, A. et al. Safety, efficacy, and biomarker analyses of dostarlimab in patients with endometrial cancer: interim results of the phase I GARNET study. Clin. Cancer Res. 29, 4564–4574 (2023).
Berton, D. et al. Antitumor activity of dostarlimab in patients with mismatch repair-deficient/microsatellite instability-high tumors: a combined analysis of two cohorts in the GARNET study. J. Clin. Oncol. 39, 2564–2564 (2021).
Overman, M. J. et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J. Clin. Oncol. 36, 773–779 (2018).
Maio, M. et al. Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study. Ann. Oncol. 33, 929–938 (2022).
Marabelle, A. et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J. Clin. Oncol. 38, 1–10 (2020).
Taïeb, J. et al. Efficacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient advanced pancreatic adenocarcinoma: an AGEO European Cohort. Eur. J. Cancer 188, 90–97 (2023).
Coston, T. et al. Efficacy of immune checkpoint inhibition and cytotoxic chemotherapy in mismatch repair-deficient and microsatellite instability-high pancreatic cancer: mayo clinic experience. JCO Precis. Oncol. 7, e2200706 (2023).
Westin, S. N. et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: the phase III DUO-E trial. J. Clin. Oncol. 42, 283–299 (2017).
Mirza, M. R. et al. Dostarlimab for primary advanced or recurrent endometrial cancer. N. Engl. J. Med. 388, 2145–2158 (2023).
Colombo, N. et al. Atezolizumab and chemotherapy for advanced or recurrent endometrial cancer (AtTEnd): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 25, 1135–1146 (2024).
Eskander, R. et al. Overall survival and progression-free survival by PD-L1 status among endometrial cancer patients treated with pembrolizumab plus carboplatin/paclitaxel as compared to carboplatin/paclitaxel plus placebo in the NRG GY018 trial. Gynecol. Oncol. 190, S5 (2024).
Diaz, L. A. et al. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 23, 659–670 (2022).
André, T. et al. Pembrolizumab versus chemotherapy in microsatellite instability-high or mismatch repair–deficient metastatic colorectal cancer: 5-year follow-up from the randomized phase 3 KEYNOTE-177 study. Ann. Oncol. 36, 277–284 (2024).
Taïeb, J. et al. Avelumab vs standard second-line chemotherapy in patients with metastatic colorectal cancer and microsatellite instability: a randomized clinical trial. JAMA Oncol. 9, 1356–1363 (2023).
Lenz, H. J. et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the phase II checkmate 142 study. J. Clin. Oncol. 40, 161–170 (2022).
Andre, T. et al. Nivolumab plus ipilimumab in microsatellite-instability-high metastatic colorectal cancer. N. Engl. J. Med. 391, 2014–2026 (2024).
André, T. et al. Nivolumab plus ipilimumab versus nivolumab in microsatellite instability-high metastatic colorectal cancer (CheckMate 8HW): a randomised, open-label, phase 3 trial. Lancet 405, 383–395 (2025).
Mazzoli, G. et al. Prognostic impact of performance status on the outcomes of immune checkpoint inhibition strategies in patients with dMMR/MSI-H metastatic colorectal cancer. Eur. J. Cancer 172, 171–181 (2022).
Fucà, G. et al. Ascites and resistance to immune checkpoint inhibition in dMMR/MSI-H metastatic colorectal and gastric cancers. J. Immunother. Cancer 10, e004001 (2022).
Corti, F. et al. The pan-immune-inflammation value in microsatellite instability-high metastatic colorectal cancer patients treated with immune checkpoint inhibitors. Eur. J. Cancer 150, 155–167 (2021).
Flecchia, C. et al. Primary resistance to immunotherapy in patients with a dMMR/MSI metastatic gastrointestinal cancer: who is at risk? An AGEO real-world study. Br. J. Cancer 130, 442–449 (2024).
André, T. et al. KEYSTEP-008: phase II trial of pembrolizumab-based combination in MSI-H/dMMR metastatic colorectal cancer. Future Oncol. 19, 2445–2452 (2023).
Ambrosini, M. et al. BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer. Eur. J. Cancer 210, 114290 (2024).
Elez, E. et al. SEAMARK: phase II study of first-line encorafenib and cetuximab plus pembrolizumab for MSI-H/dMMR BRAFV600E-mutant mCRC. Future Oncol. https://doi.org/10.2217/fon-2022-1249 (2023).
Rha, S. Y. et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 24, 1181–1195 (2023).
Shitara, K. et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature 603, 942–948 (2022).
Pietrantonio, F. et al. Predictive role of microsatellite instability for PD-1 blockade in patients with advanced gastric cancer: a meta-analysis of randomized clinical trials. ESMO Open. 6, 100036 (2021).
Yoon, H. H. et al. Association of PD-L1 expression and other variables with benefit from immune checkpoint inhibition in advanced gastroesophageal cancer: systematic review and meta-analysis of 17 phase 3 randomized clinical trials. JAMA Oncol. 8, 1456–1465 (2022).
Janjigian, Y. Y. et al. First-line nivolumab plus chemotherapy for advanced gastric, gastroesophageal junction, and esophageal adenocarcinoma: 3-year follow-up of the phase III CheckMate 649 trial. J. Clin. Oncol. 42, 2012–2020 (2024).
Janjigian, Y. Y. et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet 398, 27–40 (2021).
Leone, A. G. et al. Immune checkpoint inhibitors in advanced gastroesophageal adenocarcinoma: a series of patient-level meta-analyses in different programmed death-ligand 1 subgroups. ESMO Open 9, 103962 (2024).
Muro, K. et al. 1513MO A phase II study of nivolumab plus low dose ipilimumab as first -line therapy in patients with advanced gastric or esophago-gastric junction MSI-H tumor: first results of the NO LIMIT study (WJOG13320G/CA209-7W7). Ann. Oncol. 34, S852–S853 (2023).
Shitara, K. et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 6, 1571–1580 (2020).
Powell, M. A., Bjørge, L., Willmott, L. & Mirza, R. Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin–paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial. Ann. Oncol. 35, 728–738 (2024).
Bogani, G. et al. Adding immunotherapy to first-line treatment of advanced and metastatic endometrial cancer. Ann. Oncol. 35, 414–428 (2024).
Mirza, M. et al. Dostarlimab plus chemotherapy followed by dostarlimab plus niraparib maintenance therapy among patients with primary advanced or recurrent endometrial cancer in the ENGOT-EN6-NSGO/GOG-3031/RUBY trial. Gynecol. Oncol. 190, S6 (2024).
Pignata, S. et al. 39MO Phase III ENGOT-En9/LEAP-001 study: Lenvatinib + pembrolizumab (LEN/PEMBRO) vs chemotherapy (chemo) as first-line (1L) therapy for advanced or recurrent endometrial cancer. ESMO Open. 9, 103539 (2024).
US National Library of Medicine. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT05112601 (2024).
Abida, W. et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 5, 471–478 (2019).
Lenis, A. T. et al. Microsatellite instability, tumor mutational burden, and response to immune checkpoint blockade in patients with prostate cancer. Clin. Cancer Res. 30, 3894–3903 (2024).
André, T. et al. Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142. Ann. Oncol. 33, 1052–1060 (2022).
Colle, R. et al. BRAFV600E/RAS mutations and Lynch syndrome in patients with MSI-H/dMMR metastatic colorectal cancer treated with immune checkpoint inhibitors. Oncologist 28, 771–779 (2023).
Toboni, M. D. et al. Differential outcomes and immune checkpoint inhibitor response among endometrial cancer patients with MLH1 hypermethylation versus MLH1 ‘Lynch-like’ mismatch repair gene mutation. Gynecol. Oncol. 177, 132–141 (2023).
Mirza, M. R. et al. Post hoc analysis of progression-free survival (PFS) and overall survival (OS) by mechanism of mismatch repair (MMR) protein loss in patients with endometrial cancer (EC) treated with dostarlimab plus chemotherapy in the RUBY trial. J. Clin. Oncol. 42, 5606–5606 (2024).
Eskander, R. N. et al. LBA43 Updated response data and analysis of progression free survival by mechanism of mismatch repair loss in endometrial cancer (EC) patients (pts) treated with pembrolizumab plus carboplatin/paclitaxel (CP) as compared to CP plus placebo (PBO) in the NRG GY018 trial. Ann. Oncol. 34, S1284 (2023).
Khushman, M. M. et al. Differential responses to immune checkpoint inhibitors are governed by diverse mismatch repair gene alterations. Clin. Cancer Res. 30, 1906–1915 (2024).
Alouani, E. L. et al. 143P Efficacy of immunotherapy in gastro-intestinal (GI) tumors with mismatch repair deficient (MMRd) unusual phenotype. Ann. Oncol. 35, S272 (2024).
Schrock, A. B. et al. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSI-high metastatic colorectal cancer. Ann. Oncol. 30, 1096–1103 (2019).
Manca, P. et al. Tumour mutational burden as a biomarker in patients with mismatch repair deficient/microsatellite instability-high metastatic colorectal cancer treated with immune checkpoint inhibitors. Eur. J. Cancer 187, 15–24 (2023).
Kwon, M. et al. Determinants of response and intrinsic resistance to PD-1 blockade in microsatellite instability-high gastric cancer. Cancer Discov. 11, 2168–2185 (2021).
Ratovomanana, T. et al. Prediction of response to immune checkpoint blockade in patients with metastatic colorectal cancer with microsatellite instability. Ann. Oncol. 34, 703–713 (2023).
Bortolomeazzi, M. et al. Immunogenomics of colorectal cancer response to checkpoint blockade: analysis of the KEYNOTE 177 trial and validation cohorts. Gastroenterology 161, 1179–1193 (2021).
Mandal, R. et al. Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response. Science 364, 485–491 (2019).
Gallois, C. et al. Transcriptomic signatures of MSI-high metastatic colorectal cancer predict efficacy of immune checkpoint inhibitors. Clin. Cancer Res. 29, 3771–3778 (2023).
Grau Bejar, J. F. et al. Immune predictors of response to immune checkpoint inhibitors in mismatch repair-deficient endometrial cancer. J. Immunother. Cancer 12, e009143 (2024).
Middha, S. et al. Majority of B2M -mutant and -deficient colorectal carcinomas achieve clinical benefit from immune checkpoint inhibitor therapy and are microsatellite instability-high. JCO Precis. Oncol. 3, 1–14 (2019).
Chida, K. et al. A low tumor mutational burden and PTEN mutations are predictors of a negative response to PD-1 blockade in MSI-H/dMMR gastrointestinal tumors. Clin. Cancer Res. 27, 3714–3724 (2021).
Wang, Z. et al. Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer. J. Immunother. Cancer 10, e004703 (2022).
Wang, Z. et al. Mutations of PI3K–AKT–mTOR pathway as predictors for immune cell infiltration and immunotherapy efficacy in dMMR/MSI-H gastric adenocarcinoma. BMC Med. 20, 1–15 (2022).
Collins, N. B. et al. PI3K activation allows immune evasion by promoting an inhibitory myeloid tumor microenvironment. J. Immunother. Cancer 10, e003402 (2022).
Patel, S. P. et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N. Engl. J. Med. 388, 813–823 (2023).
Blank, C. U. et al. Neoadjuvant nivolumab and ipilimumab in resectable stage III melanoma. N. Engl. J. Med. 391, 1696–1708 (2024).
Xu, R.-H. et al. Neoadjuvant treatment of IBI310 (anti-CTLA-4 antibody) plus sintilimab (anti-PD-1 antibody) in patients with microsatellite instability-high/mismatch repair-deficient colorectal cancer: results from a randomized, open-labeled, phase Ib study. J. Clin. Oncol. 42, 3505–3505 (2024).
de la Fouchardiere, C. et al. 504O IMHOTEP phase II trial of neoadjuvant pembrolizumab in dMMR/MSI tumors: results of the colorectal cancer cohort. Ann. Oncol. 35, S428–S481 (2024).
Qvortrup, C. et al. Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: final analysis of the RESET-C study. J. Clin. Oncol. 43, 19–19 (2025).
de Gooyer, P. G. M. et al. Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial. Nat. Med. 30, 3284–3290 (2024).
Chen, G. et al. Neoadjuvant PD-1 blockade with sintilimab in mismatch-repair deficient, locally advanced rectal cancer: an open-label, single-centre phase 2 study. Lancet Gastroenterol. Hepatol. 8, 422–431 (2023).
Platt, J. R. et al. Risk of bowel obstruction in patients with colon cancer responding to immunotherapy: an international case series. ESMO Open. 9, 103698 (2024).
Chalabi, M. et al. LBA24 Neoadjuvant immunotherapy in locally advanced MMR-deficient colon cancer: 3-year disease-free survival from NICHE-2. Ann. Oncol. 35, S1217–S1218 (2024).
Hong, E. K. et al. Colon cancer CT staging according to mismatch repair status: Comparison and suggestion of imaging features for high-risk colon cancer. Eur. J. Cancer 174, 165–175 (2022).
Ludford, K. et al. Neoadjuvant pembrolizumab in localized microsatellite instability high/deficient mismatch repair solid tumors. J. Clin. Oncol. 41, 2181–2190 (2023).
Cercek, A. et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer. N. Engl. J. Med. 386, 2363–2376 (2022).
Cercek, A. et al. Durable complete responses to PD-1 blockade alone in mismatch repair deficient locally advanced rectal cancer. J. Clin. Oncol. 42, LBA3512–LBA3512 (2024).
Venook, A. P. et al. NCCN Guidelines Version 1.2025 Rectal Cancer (NCCN, 2025).
Eerkens, A. L. et al. Neoadjuvant immune checkpoint blockade in women with mismatch repair deficient endometrial cancer: a phase I study. Nat. Commun. 15, 1–17 (2024).
André, T. et al. Antitumor activity and safety of dostarlimab monotherapy in patients with mismatch repair deficient solid tumors: a nonrandomized controlled trial. JAMA Netw. Open. 6, e2341165–e2341165 (2023).
Le, D. T. et al. Pembrolizumab for previously treated, microsatellite instability–high/mismatch repair–deficient advanced colorectal cancer: final analysis of KEYNOTE-164. Eur. J. Cancer 186, 185–195 (2023).
Overman, M. J. et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 18, 1182–1191 (2017).
Overman, M. J. et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) in previously treated patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC): long-term follow-up. J. Clin. Oncol. 37, 635–635 (2019).
Oaknin, A. et al. Dostarlimab in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability-high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC): the GARNET study. J. Clin. Oncol. 40, 5509–5509 (2022).
Antill, Y. et al. Clinical activity of durvalumab for patients with advanced mismatch repair-deficient and repair-proficient endometrial cancer. A nonrandomized phase 2 clinical trial. J. Immunother. Cancer 9, e002255 (2021).
Eskander, R. N. et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. N. Engl. J. Med. 388, 2159–2170 (2023).
Mirza, M. R. et al. 38MO Progression-free survival (PFS) in primary advanced or recurrent endometrial cancer (pA/rEC) in the overall and mismatch repair proficient (MMR/MSS) populations and in histological and molecular subgroups: Results from part 2 of the RUBY trial. ESMO Open. 9, 103538 (2024).
Fuchs, C. S. et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 4, e180013–e180013 (2018).
Shitara, K. et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 392, 123–133 (2018).
Hu, H. et al. Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial. Lancet Gastroenterol. Hepatol. 7, 38–48 (2022).
P. M. Kasi et al. 8MO Neoadjuvant botensilimab (BOT) plus balstilimab (BAL) in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial. Ann. Oncol. 35, S1-S74 (2024).
Shiu, K.-K. et al. NEOPRISM-CRC: Neoadjuvant pembrolizumab stratified to tumour mutation burden for high risk stage 2 or stage 3 deficient-MMR/MSI-high colorectal cancer. J. Clin. Oncol. 42, LBA3504–LBA3504 (2024).
Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).
Niu, B. et al. MSIsensor: microsatellite instability detection using paired tumor-normal sequence data. Bioinformatics 30, 1015–1016 (2014).
Chakravarty, D. et al. OncoKB: a precision oncology knowledge base. JCO Precis. Oncol. 2017, 1–16 (2017).
Kang, Y. J. et al. A scoping review and meta-analysis on the prevalence of pan-tumour biomarkers (dMMR, MSI, high TMB) in different solid tumours. Sci. Rep. 12, 1–13 (2022).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to all aspects of the article.
Corresponding author
Ethics declarations
Competing interests
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.
Peer review
Peer review information
Nature Reviews Clinical Oncology thanks M. Cecchini, who co-reviewed with F. Yasin; M. Kloor; L. Shen; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41571-025-01015-z
