An oncogenic SUMO program restricts the targetable cancer immunopeptidome

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. Additionally, SUMOylation altered TAP1 transporter binding preferences, thereby mimicking viral immune evasion strategies. As an actionable application, pharmacological inhibition of SUMOylation unmasked the targetable immunopeptidome and enhanced the tumor cell susceptibility to T cell killing. These findings highlight SUMOylation as a critical regulator of the adaptive antitumor immune response. We propose SUMO inhibition as a rational strategy to enhance immunogenic peptide presentation for more effective cancer immunotherapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Blood

DISEASE(S): Lymphoma

SUBMITTER: Marieluise Kirchner  

LAB HEAD: Philipp Mertins

PROVIDER: PXD060641 | Pride | 2026-04-06

REPOSITORIES: Pride