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Aberrant SUMOylation 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. 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 and enhanced the tumor cell susceptibility to T cell killing. These findings highlight SUMOylation as a critical regulator of the adaptive anti-tumor immune response. We propose SUMO inhibition as a strategic approach to enhance immunogenic peptide presentation, thereby improving the efficacy of cancer immunotherapies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Cell Suspension Culture

DISEASE(S): Lymphoma

SUBMITTER: Martin Klatt

LAB HEAD: Martin Klatt

PROVIDER: PXD061196 | Pride | 2026-01-25

REPOSITORIES: Pride

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			Action	DRS
	BC-1_HLA-I_D2.raw	Raw
	BC-1_HLA-I_D2.raw_20250213_Byonic.mgf	Mgf
	BC-1_HLA-I_D2.raw_20250213_Byonic.mzid	Mzid
	BC-1_HLA-I_E5.raw	Raw
	BC-1_HLA-I_E5.raw_20250213_Byonic.mgf	Mgf

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Aberrant SUMOylation restricts the targetable cancer immunopeptidome

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