{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:18:55Z","timestamp":1787635135684,"version":"build-2736575974"},"reference-count":95,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,22]],"date-time":"2026-08-22T00:00:00Z","timestamp":1787356800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour\u2019s capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, \u03b22-microglobulin (\u03b22-m), or interferon-\u03b3 (IFN-\u03b3) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies.<\/jats:p>","DOI":"10.3390\/cells15171513","type":"journal-article","created":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T08:03:41Z","timestamp":1787558621000},"page":"1513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cancer Immune Responsiveness and MHC Class I Antigen Presentation: Mechanisms of Immune Escape and Immunotherapy Resistance in Gastrointestinal Cancers"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0925-742X","authenticated-orcid":false,"given":"Fabio","family":"Grizzi","sequence":"first","affiliation":[{"name":"Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Milan, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"Chiriva-Internati","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology & Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7810-5011","authenticated-orcid":false,"given":"Mohamed A. A. A.","family":"Hegazi","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9186-8400","authenticated-orcid":false,"given":"Federica","family":"Rubbino","sequence":"additional","affiliation":[{"name":"Laboratory of Macrophage Dynamics, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-3794","authenticated-orcid":false,"given":"Fabio","family":"Pasqualini","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, 20089 Milan, Italy"},{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3909-9012","authenticated-orcid":false,"given":"Marco","family":"Spadaccini","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Andreozzi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8780-8832","authenticated-orcid":false,"given":"Miriana","family":"Mercurio","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1522-5448","authenticated-orcid":false,"given":"Federico","family":"Cassano","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3922-1148","authenticated-orcid":false,"given":"Maria","family":"Terrin","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesare","family":"Hassan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Bresalier","sequence":"additional","affiliation":[{"name":"Departments of Gastroenterology, Hepatology & Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Repici","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Carrara","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Division of Gastroenterology and Digestive Endoscopy, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/s41568-021-00347-z","article-title":"Systemic immunity in cancer","volume":"21","author":"Allen","year":"2021","journal-title":"Nat. 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