Neoantigen-based cancer immunotherapies hold great promise, yet their success is often hindered by inefficient neoantigen presentation on HLA-I complexes. Tumour-derived neoantigens must compete with an overwhelming abundance of self-peptides, ultimately leading to poor neoantigen visibility. Current strategies such as IFN-γ treatment attempt to enhance antigen presentation collectively but fail to specifically boost neo-peptide presentation. As a result, most low abundant neoantigens remain overshadowed. While extensive efforts have been dedicated to identifying neoantigens, these efforts have limited success if poor neoantigen presentation remains a fundamental barrier.
The proteasome plays a central role in antigen processing, however its lack of specificity for mutant proteins results in indiscriminate degradation and self-peptide saturation. We hypothesized that specific neoantigens can be enriched by biasing proteasomal degradation towards cancer-specific proteins. Targeted protein degraders (TPDs) such as PROTACs have emerged as powerful tools for eliminating oncogenic proteins via the proteasome. Yet, their potential to modulate tumour immunopeptidome remains largely unexplored. Using PROTACs, we mechanistically investigated this approach by directing proteasomal activity against tumour-associated STAT3 protein. We observed specific enrichment of STAT3-derived HLA-I peptides upon PROTAC treatment, concomitant with the reduction in proteome STAT3 levels. These initial findings establish a direct mechanistic link between targeted proteasomal degradation and selective antigen presentation, supporting a new strategy to repurpose PROTAC degraders beyond protein knockdown. Ongoing studies are extending this approach to mutant cancer proteins to uncover whether this increase in neoantigen visibility heightens T-cell responses. Collectively, our work positions TPD as a tunable lever to reshape the cancer immunopeptidome and potentiate immunotherapeutic response.