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journal article·2026-03Open access

Aberrant SUMOylation Restricts the Targetable Cancer Immunopeptidome

Uta M. Demel, Anna Meurer, Badeel Kh. Q. Zaghla, Bilge Atay, Daniel Steiert, Luca V. Hummel, Konstandina Isaakidis, Chuanbing Zang, Michael Korenkov, Marlon Schielin, Schayan Yousefian, Shima Mecklenbräuker, Marieluise Kirchner, Simon Haas, Antonia Busse, Philipp Mertins, Stefan Müller, Matthias Wirth, Martin G. Klatt, Ulrich Keller

Advanced Science· Volume 13· Issue 17
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Source abstract

Abstract

ABSTRACT A balanced SUMOylation equilibrium safeguards the functional anti‐tumor immune response. Oncogene activation drives SUMOylation, rendering aberrant SUMOylation a hallmark of cancer. To delineate the impact of activated SUMOylation on the tumor‐immune synapse, we applied HLA class‐I‐targeted ligandomics and identified a function of activated SUMOylation in restricting the immunopeptidome landscape. Importantly, aberrant SUMOylation suppressed a unique HLA‐I peptide and oncoprotein‐derived 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‐tumor immune response. We propose SUMOylation inhibition as a strategy to enhance immunogenic peptide presentation, thereby improving the efficacy of cancer immunotherapies.
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Research context

OpenAlex topics: vaccines and immunoinformatics approaches · Ubiquitin and proteasome pathways · Peptidase Inhibition and Analysis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu Berlin Berlin Germany

Max‐Delbrück‐Center For Molecular Medicine Berlin Germany

Clinician Scientist Program Berlin Institute of Health (BIH) Berlin Germany

Berlin Institute for Medical Systems Biology Max Delbrück Center For Molecular Medicine in the Helmholtz Association Berlin Germany

Berlin Institute of Health (BIH) At Charité – Universitätsmedizin Berlin Berlin Germany

German Cancer Consortium (DKTK) partner site Berlin German Cancer Research Center (DKFZ) Heidelberg Germany

Cluster of Excellence Immunoprecept Charité – Universitätsmedizin Berlin Berlin Germany

Institute of Biochemistry II, Goethe University Frankfurt Medical School Frankfurt Germany

German Cancer Consortium (DKTK) partner site Frankfurt/ Mainz German Cancer Research Center (DKFZ) Heidelberg Germany

Department of General, Visceral and Pediatric Surgery University Medical Center Göttingen Göttingen Germany

National Center for Tumor Diseases (NCT), partner site Berlin German Cancer Research Center (DKFZ) Heidelberg Germany

Funding

Else Kröner-Fresenius-Stiftung · Wilhelm Sander-Stiftung · Stiftung Charité · Deutsches Krebsforschungszentrum · Hector Stiftung · Deutsche Krebshilfe · Deutsche Forschungsgemeinschaft

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