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MMR-deficient cancer cells overexpress immune checkpoint proteins, including PD-1 and PD-L1, enabling pharmacologic targeting to restore cytotoxic antitumor immunity. This review explains MSI’s role in colorectal cancer tumor biology, emphasizing immune microenvironment interactions and therapeutic 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Actionability—Lessons from Colorectal Cancer  \nLuana Greco 1, Federica Rubbino 1, Arianna Dal Buono 2 and Luigi Laghi 1,3, *  \nCitation: Greco, L.; Rubbino, F.; Dal Buono, A.; Laghi, L. Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability—Lessons from Colorectal Cancer. Genes 2023, 14, 1169. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)genes14061169  \nAcademic Editors: Lucio Bertario, Bernardo Bonanni and  \nDavide Serrano  \nReceived: 27 April 2023  \nRevised: 22 May 2023  \nAccepted: 24 May 2023  \nPublished: 27 May 2023  \nCopyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56,  \n20089 Rozzano, Italy; luana.greco@humanitasresearch.it (L.G.); federica.rubbino@humanitasresearch.it (F.R.)  \n2 Division of Gastroenterology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy; arianna.dalbuono@humanitas.it  \n3 Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy  \n* Correspondence: luigi.laghi@humanitas.it  \nAbstract: Microsatellite instability (MSI) can be found in 15–20% of all colorectal cancers (CRC) and is the key feature of a defective DNA mismatch repair (MMR) system. Currently, MSI has been established as a unique and pivotal biomarker in the diagnosis, prognosis, and treatment of CRC. MSI tumors display a strong lymphocytic activation and a shift toward a tumoral microenvironment restraining metastatic potential and ensuing in a high responsiveness to immunotherapy of MSI CRC. Indeed, neoplastic cells with an MMR defect overexpress several immune checkpoint proteins, such as programmed death-1 (PD-1) and programmed death-ligand 1(PD-L1), that can be pharmacologically targeted, allowing for the revival the cytotoxic immune response toward the tumor. This review aims to illustrate the role of MSI in the tumor biology of colorectal cancer, focusing on the immune interactions with the microenvironment and their therapeutic implications.  \nKeywords: microsatellite instability; DNA mismatch repair; colorectal cancer; hereditary syndrome; immunotherapy; microenviroment; immune checkpoint; checkpoint inhibitors  \n1. Introduction  \nColorectal cancer (CRC) is the second most common non-sex-dependent type of cancer, accounting for over 500.000 new cases and being the second most common cause of cancer death in Europe in 2020 [1] . These rates feed the need of implementing screening policies [2] altogether with the knowledge of the biological bases of its initiation and progression pathways to appropriately restrain morbidity and mortality.  \nCRC is a heterogeneous and multi-factorial disease; however, it is classifiable by its genetic bases: alongside the classical model of tumorigenesis (i.e., the chromosomal instability pathway, or CIN), a subset of CRC is marked by the presence of microsatellite instability (MSI), accounting for 15% of all cases (overall 3% being hereditary and the remaining 12% sporadic) [3,4] . The molecular phenotype of MSI was first recognized in the early 1990s [5]; such a phenotype originates from the presence of deletions in repetitive DNA sequences (called microsatellites) due to a dysfunction of the DNA mismatch repair system (MMR), the highly conserved system for correcting the errors that develop during DNA replication. A defective MMR (dMMR) system ensues, therefore, in constantly high mutational rates and instability of the tumor genome, leading to the","cbCailZDsnPSeKVx","https://ap.wps.com/l/cbCailZDsnPSeKVx","pdf",2173316,"English","# Introduction\n# Microsatellite Instability and Defective DNA Mismatch Repair\n# Hereditary Origins and Lynch Syndrome\n# Clinical Features and Prognostic Implications","[{\"question\":\"What is microsatellite instability (MSI) and how common is it in colorectal cancer?\",\"answer\":\"MSI is a key feature of defective DNA mismatch repair and is present in about 15–20% of colorectal cancers.\"},{\"question\":\"Why are MSI tumors often responsive to immunotherapy?\",\"answer\":\"MSI tumors tend to show immune activation and overexpression of immune checkpoint proteins such as PD-1 and PD-L1, which can be pharmacologically targeted to restore cytotoxic immune responses.\"},{\"question\":\"How does Lynch syndrome relate to MSI colorectal cancer?\",\"answer\":\"Lynch syndrome results from germline pathogenic variants in MMR genes (e.g., MLH1, PMS2, MSH2, MSH6, or EPCAM deletions), predisposing patients to colorectal and other extracolonic cancers.\"}]","Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability - Lessons from Colorectal Cancer | PDF",1790250857]