{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T21:48:39Z","timestamp":1793742519406,"version":"4.6.1"},"reference-count":91,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":223,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Immunology Research"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:p>\n                    Colorectal cancer (CRC) remains a leading cause of cancer\u2010related mortality worldwide. Approximately 15% of localized and 5% of metastatic cases exhibit mismatch repair deficiency (dMMR) or high microsatellite instability (MSI\u2010H). While immune checkpoint inhibitors (ICIs) have revolutionized the first\u2010line treatment for this subgroup, 15%\u201346% of patients experience primary resistance, and a subset of responders eventually acquires resistance. This review synthesizes the multifaceted mechanisms underlying ICI resistance in dMMR\/MSI\u2010H CRC. We delineate tumor\u2010intrinsic alterations, including defects in the antigen presentation machinery (specifically transporter associated with antigen processing [TAP]1\/TAP2 and \u03b2\n                    <jats:sub>2<\/jats:sub>\n                    \u2010microglobulin [\u03b2\n                    <jats:sub>2<\/jats:sub>\n                    m]), oncogenic signaling via the Wnt\/\u03b2\u2010catenin and JAK\/STAT pathways, and epigenetic remodeling involving ARID1A. Furthermore, we explore the role of the immunosuppressive tumor microenvironment (TME), characterized by T\u2010cell exclusion and myeloid\u2010derived suppressor cell (MDSC) accumulation. To address these barriers, we evaluate the clinical potential of third\u2010generation ICIs targeting lymphocyte activation gene 3 (LAG\u20103), T\u2010cell immunoglobulin and mucin\u2010domain\u2010containing\u20103 (TIM\u20103), and TIGIT, as well as emerging biomarker strategies such as gut microbiome modulation and circulating tumor DNA (ctDNA) dynamics. By integrating these mechanistic insights with novel therapeutic approaches, including bispecific antibodies (BsAbs) and adoptive cell transfer, this review aims to provide a roadmap for overcoming resistance and advancing precision immunotherapy in dMMR\/MSI\u2010H CRC.\n                  <\/jats:p>","DOI":"10.1155\/jimr\/5084171","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T06:37:16Z","timestamp":1786603036000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immunotherapy Resistance in dMMR\/MSI\u2010H Colorectal Cancer: Unraveling Mechanisms and Exploring Overcoming 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