{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T05:16:08Z","timestamp":1788066968168,"version":"build-2784847793"},"reference-count":183,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA271533"],"award-info":[{"award-number":["R01CA271533"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA260698"],"award-info":[{"award-number":["R01CA260698"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01CA275089"],"award-info":[{"award-number":["R01CA275089"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.S. Department of Veterans Affairs (VA), Biomedical Laboratory Research and Development Service","award":["I01 BX005094"],"award-info":[{"award-number":["I01 BX005094"]}]},{"award":["I01 BX005094"],"award-info":[{"award-number":["I01 BX005094"]}],"id":[{"id":"https:\/\/ror.org\/05rsv9s98","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Colorectal cancer (CRC) remains a major cause of cancer morbidity and mortality. Immune checkpoint inhibitors (ICIs) have transformed the treatment of microsatellite instability-high\/mismatch repair-deficient (MSI-H\/dMMR) CRC, yet most CRCs are microsatellite-stable\/mismatch repair-proficient (MSS\/pMMR) and remain poorly responsive to immunotherapy. MicroRNAs (miRNAs) are well positioned to influence this biology because individual miRNAs can coordinate multiple tumor-intrinsic and microenvironmental programs that shape antitumor immunity. Rather than cataloging miRNAs one by one, this review organizes the evidence around the major barriers that sustain an immune-cold CRC microenvironment: altered checkpoint and costimulatory signaling, defective antigen presentation, impaired effector T-cell access and function, suppressive myeloid and stromal compartments, and extracellular vesicle (EV)-mediated intercellular communication. We also critically assess tissue and circulating miRNA signatures as candidate biomarkers of ICI response and discuss therapeutic approaches based on miRNA mimics, inhibitors, and targeted delivery platforms. The available evidence supports a biologically compelling role for miRNA networks in CRC immune regulation, but clinical translation remains limited by context dependence, delivery, off-target effects, and the lack of treatment-linked validation in CRC cohorts.<\/jats:p>","DOI":"10.3390\/genes17091025","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:27:46Z","timestamp":1787920066000},"page":"1025","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MicroRNAs in Colorectal Cancer Immunotherapy: Biomarkers, Resistance Mechanisms, and Strategies to Convert \u201cCold\u201d Tumors to \u201cHot\u201d"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9870-7968","authenticated-orcid":false,"given":"Jin","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1231-2385","authenticated-orcid":false,"given":"Ruixia","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3681-9352","authenticated-orcid":false,"given":"Yaguang","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, USA"},{"name":"Innovations in Drug Discovery (IDD) Program, College of Pharmacy, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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