# Aberrant SUMOylation Restricts the Targetable Cancer Immunopeptidome

## TL;DR

Abnormal SUMOylation limits the range of cancer peptides presented to the immune system, helping cancer cells avoid detection, but inhibiting SUMOylation can restore immune recognition and improve cancer immunotherapy.

## Contribution

This study reveals that SUMOylation inhibition can unmask hidden cancer peptides and enhance immune response, offering a novel strategy for cancer immunotherapy.

## Key findings

- Aberrant SUMOylation suppresses HLA-I peptides and neoepitopes, allowing cancer cells to evade T cell detection.
- SUMOylation inhibition increases immunopeptidome diversity and tumor cell susceptibility to T cell killing.
- Pharmacological SUMOylation inhibition reshapes the immune cell landscape in preclinical cancer models.

## 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.

Pharmacological SUMOylation inhibition (SUMOi) counteracts tumor immune evasion by unmasking an immunogenic HLA‐I peptide and neoepitope repertoire. By restoring HLA‐I ligand availability through increased antigen processing and presentation, enhanced proteasomal cleavage, and modulated TAP1 peptide affinity, SUMOi boosts tumor immunogenicity, resulting in improved T cell infiltration and cytotoxicity across multiple preclinical cancer models.