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This review describes the function of the Major Histocompatibility Complex class I antigen presentation machinery and highlights how its perturbation can lead to compromised immune function and disease progression in the context of cancer. We categorize these perturbations into four distinct mechanistic levels: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. This enables an integrated view of their functional impact on immune recognition, supporting therapeutic efforts to target antigen presentation or exploit these alterations in cancer.<\/jats:p>","DOI":"10.3390\/cells15070653","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:40:31Z","timestamp":1775554831000},"page":"653","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Messing with Signal 1: How Perturbed MHC Class I Antigen Presentation Contributes to Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-6195","authenticated-orcid":false,"given":"Myriam","family":"Lawand","sequence":"first","affiliation":[{"name":"Department of Biology, Faculty of Arts and Sciences, Souk El-Gharb Campus, University of Balamand, Aley 1501, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salman","family":"Al Rayess","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Arts and Sciences, Souk El-Gharb Campus, University of Balamand, Aley 1501, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rawad","family":"Jaber","sequence":"additional","affiliation":[{"name":"Department of Biology, Faculty of Arts and Sciences, Souk El-Gharb Campus, University of Balamand, Aley 1501, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3782-0750","authenticated-orcid":false,"given":"Peter","family":"van Endert","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris Cit\u00e9, Institut national de la sant\u00e9 et de la recherche m\u00e9dicale (INSERM), Centre national de la recherche scientifique (CNRS), Institut Necker-Enfants Malades, 160 rue de Vaugirard, F-75015 Paris, France"},{"name":"Service Immunologie Biologique, Assistance Publique-H\u00f4pitaux de Paris (AP-HP), H\u00f4pital Universitaire Necker-Enfants Malades, 149 rue de S\u00e8vres, F-75015 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0092-8674(01)00449-4","article-title":"Dendritic cells: Specialized and regulated antigen processing machines","volume":"106","author":"Mellman","year":"2001","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8131","DOI":"10.1007\/s00432-023-04737-8","article-title":"Cancer immune escape: The role of antigen presentation machinery","volume":"149","author":"Kallingal","year":"2023","journal-title":"J. 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