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Oncogene activation drives SUMOylation, rendering aberrant SUMOylation a hallmark of cancer. To delineate the impact of activated SUMOylation on the tumor\u2010immune synapse, we applied HLA class\u2010I\u2010targeted ligandomics and identified a function of activated SUMOylation in restricting the immunopeptidome landscape. Importantly, aberrant SUMOylation suppressed a unique HLA\u2010I peptide and oncoprotein\u2010derived neoepitope repertoire, enabling cancer cells to evade T cell immune surveillance. Mechanistically, SUMOylation impaired the immunoproteasome constitution and proteolytic activity, thus limiting the diversity of the peptide landscape. Further, SUMOylation altered TAP1 transporter binding preferences, thereby mimicking viral immune evasion strategies. As an actionable application, pharmacological inhibition of SUMOylation unmasked the targetable immunopeptidome, enhanced the tumor cell susceptibility to T cell killing and substantially reshaped the immune cell landscape. These findings highlight SUMOylation as a critical regulator of the adaptive anti\u2010tumor immune response. We propose SUMOylation inhibition as a strategy to enhance immunogenic peptide presentation, thereby improving the efficacy of cancer immunotherapies.<\/jats:p>","DOI":"10.1002\/advs.202511449","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:34:41Z","timestamp":1769060081000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Aberrant SUMOylation Restricts the Targetable Cancer Immunopeptidome"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6480-4185","authenticated-orcid":false,"given":"Uta M.","family":"Demel","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology and Cancer Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"},{"name":"Max\u2010Delbr\u00fcck\u2010Center For Molecular Medicine  Berlin Germany"},{"name":"Clinician Scientist Program Berlin Institute of Health (BIH)  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Meurer","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Cancer Immunology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin Corporate Member of Freie Universit\u00e4t Berlin and Humboldt\u2010Universit\u00e4t zu Berlin  Berlin Germany"},{"name":"Max\u2010Delbr\u00fcck\u2010Center For Molecular Medicine  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Badeel Kh. 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