{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T16:33:03Z","timestamp":1787502783374,"version":"build-2736575974"},"reference-count":90,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The therapeutic armamentarium for colorectal cancer (CRC) has been significantly expanded with the introduction of immunotherapy, particularly immune checkpoint inhibitors (ICIs). However, the response to immunotherapy is strongly dependent on microsatellite instability (MSI) status. Tumors with high MSI (MSI-H) and\/or mismatch repair deficiency (dMMR) exhibit high tumor mutational burden (TMB), increased neoantigen load, and enhanced immunogenicity, leading to improved responses to ICIs compared with microsatellite-stable (MSS) and\/or mismatch repair-proficient (pMMR) tumors. This has changed the treatment landscape of this small subgroup of metastatic CRC (mCRC), including the approval of pembrolizumab as a first-line option. In contrast, most mCRC cases are MSS\/pMMR and are resistant or poorly responsive to ICIs, with no established standard immunotherapy strategy. Therefore, current approaches aim to convert these \u201ccold\u201d tumors into \u201chot,\u201d immunologically active tumors. This review summarizes the distinct molecular basis of MSI phenotypes and their interaction with the tumor microenvironment, and provides relevant insights into current clinical evidence for prognostic and predictive biomarkers beyond MSI status, as well as novel therapeutic strategies to overcome resistance in MSS disease.<\/jats:p>","DOI":"10.3390\/genes17060674","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T05:50:58Z","timestamp":1781157058000},"page":"674","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Microsatellite Phenotype as a Guide for Immunotherapy in Colorectal Cancer: Current Status and Future Perspectives"],"prefix":"10.3390","volume":"17","author":[{"given":"Evangelos","family":"Koustas","sequence":"first","affiliation":[{"name":"Oncology Department, General Hospital Evangelismos, Ipsilantou 45-47, 106 76 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni-Myrto","family":"Trifylli","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3987-7112","authenticated-orcid":false,"given":"Vaios","family":"Oraiopoulos","sequence":"additional","affiliation":[{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1369-8201","authenticated-orcid":false,"given":"Michalis V.","family":"Karamouzis","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece"},{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5848-7905","authenticated-orcid":false,"given":"Panagiotis","family":"Sarantis","sequence":"additional","affiliation":[{"name":"Institute of Molecular Medicine and Biomedical Research, 115 27 Athens, Greece"},{"name":"University Clinic of Internal Medicine, General and Oncology Hospital \u201cAgioi Anargyroi\u201d, National and Kapodistrian University of Athens, Timiou Stavrou 14, 145 64 Kifisia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Koustas, E., Sarantis, P., Kyriakopoulou, G., Papavassiliou, A.G., and Karamouzis, M.V. 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