{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T08:34:59Z","timestamp":1786523699144,"version":"build-2736575974"},"reference-count":259,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) have significantly changed the treatment landscape of several gastrointestinal (GI) malignancies, particularly microsatellite instability-high (MSI-H) and mismatch repair-deficient (dMMR) tumors. However, most GI cancers remain resistant to current PD-1\/PD-L1-based immunotherapy because of complex and highly suppressive tumor microenvironments characterized by immune stromal exclusion, myeloid-driven immune suppression, defective antigen presentation, and adaptive immune resistance mechanisms. Emerging evidence suggests that alternative inhibitory pathways, including lymphocyte activation gene-3 (LAG-3), T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and V-domain Ig suppressor of T-cell activation (VISTA), contribute substantially to persistent T-cell dysfunction and resistance to checkpoint blockade. This review summarizes the immune landscape of GI malignancies and discusses the biological mechanisms underlying resistance to current ICIs. We highlight the evolving role of next-generation immune checkpoints, ongoing clinical development of novel inhibitors, and emerging combination strategies involving chemotherapy, anti-angiogenic therapy, radiation, bispecific antibodies, and tumor microenvironment modulation. In addition, we discuss current limitations in biomarker development and the growing role of circulating tumor DNA, spatial immune profiling, and multi-omics approaches in patient selection. Finally, we explore future directions aimed at improving precision immunotherapy and expanding durable responses across GI cancers.<\/jats:p>","DOI":"10.3390\/cancers18162593","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T07:57:26Z","timestamp":1786521446000},"page":"2593","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Next-Generation Immune Checkpoint Inhibitors in Gastrointestinal Cancers: Mechanisms, Resistance, and Emerging Therapeutic Strategies"],"prefix":"10.3390","volume":"18","author":[{"given":"Mariam","family":"Ismail","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Delta University for Science and Technology, Gamasa 11152, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zaid","family":"Alabed","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khaled","family":"Alhallaq","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ebtesam","family":"Al-Najjar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour","family":"Mustafa","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yacoub","family":"Aldroubi","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, The University of Jordan, Amman 11942, Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazan","family":"Hamdaneh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Methodist Healthcare System of San Antonio, TX 78229, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2337-8351","authenticated-orcid":false,"given":"Abdullah","family":"Esmail","sequence":"additional","affiliation":[{"name":"Department of Medicine, Houston Methodist Neal Cancer Center, Houston Methodist Hospital, Houston, TX 77030, USA"},{"name":"Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1053\/j.gastro.2020.02.068","article-title":"Global Burden of 5 Major Types of Gastrointestinal Cancer","volume":"159","author":"Arnold","year":"2020","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jare.2025.11.051","article-title":"Burden profiles and mortality-attributable risk factors for gastrointestinal cancers: A comprehensive analysis, 1990\u20132021","volume":"86","author":"Fan","year":"2026","journal-title":"J. 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