Project Grant R01CA295942

Yale University received a $482,312 Project Grant award from the National Cancer Institute (NCI) under the Cancer Treatment Research program (CFDA 93.395), effective April 2, 2026, through March 31, 2031. The award funds research to develop a novel therapeutic approach for inactivating regulatory T (Treg) cells through targeted protein degradation as a strategy to overcome immunotherapy resistance in cancer patients. The research builds on preliminary findings demonstrating that degradation of FOXP3 protein—a lineage-defining transcription factor in Treg cells—selectively inactivates tumor Treg cells and produces tumor shrinkage in murine melanoma models without overt toxicity. This approach addresses critical limitations of current immunotherapies, including poor tumor selectivity and lack of highly specific druggable targets, while potentially minimizing immune-related adverse events associated with overactivated immune cells.

The research conducted at Yale's West Haven, Connecticut facility will utilize genetically engineered mouse models to investigate FOXP3-dependent mechanisms in hyperproliferative tumor Treg cells and advance the development of FOXP3 protein degradation as a cancer immunotherapy. By targeting the heritability of Treg-specific gene expression across cell division, this project aims to selectively inactivate immunosuppressive cells within the tumor microenvironment, thereby enhancing anti-tumor immune responses in cancers resistant to existing immunotherapy modalities such as chimeric antigen receptor-based cell therapy, cytokine therapy, and immune checkpoint blockade.