Novel Treg inactivating approach for cancer immunotherapy via targeted protein degradation

Despite the growing success of immunotherapies, such as chimeric antigen receptor-based cell therapy, cytokine therapy, and immune checkpoint blockade (ICB), a substantial number of cancers remain unresponsive. Furthermore, these therapies can lead to off-target toxicities, known as immune-related adverse events, resulting from overactivated immune cells. This project aims to devise a novel approach for deactivating regulatory T (Treg) cells, potent immunosuppressive cells in the tumor microenvironment, as a strategy to overcome immunotherapy resistance and minimize side effects. Preclinical studies in mouse models have demonstrated that depleting Treg cells can yield robust anti-tumor effects, even in tumors resistant to other forms of immunotherapy. However, current Treg-targeting therapeutics face significant challenges, particularly a lack of highly specific druggable targets and poor tumor selectivity. Our preliminary investigation into gene transcription regulation in Treg cells has yielded promising insights that could potentially address these obstacles. Using a genetically engineered mouse model for targeted protein degradation in vivo, we revisited the role of the Treg lineage-defining transcription factor Foxp3 in mature Treg cells post-developmentally. Contrary to expectations, Foxp3 was found to be largely dispensable for maintaining mature Treg cell identity and suppressor function. Instead, Foxp3 was uniquely essential for the heritability of Treg-specific gene expression and function across cell division. Consequently, hyperproliferative tumor Treg cells were much more dependent on Foxp3 for identity and function. Notably, degrading Foxp3 protein led to tumor shrinkage in a murine model of melanoma without overt toxicity. Building on these compelling results, we propose that Foxp3 protein degradation selectively inactivates tumor Treg cells, enhancing anti-tumor immunity with minimal extra-tumor adverse effects. We outline three aims to advance understanding and develop new reagents for this potential novel cancer immunotherapy option. Aim 1 involves characterizing the efficacy and adverse effects of Foxp3 degradation-based cancer immunotherapy. Aim 2 aims to elucidate the mechanisms of Foxp3 degradation-induced tumor killing. Aim 3 focuses on developing a chemical for degrading human Foxp3 protein, paving the way for therapeutic targeting of Treg cells in the clinical setting. Completion of these aims is anticipated to significantly advance our understanding of the efficacy, safety profile, and mechanism of action of Foxp3 degradation-based cancer immunotherapy. Moreover, the research aims to provide candidate compounds for further optimization, potentially offering new therapeutic options for cancer patients resistant to existing immunotherapies. Project Number: 1R01CA295942-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Wei Hu | Institution: YALE UNIVERSITY, NEW HAVEN, CT | Award Amount: $482,312 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11296173