Enhancing the Efficacy of T-cells and immunotherapies by precision targeting of Nrf2 using PROTACs

T-cells are key players in adaptive immunity and have revolutionized immunotherapies for cancer, autoimmune, and infectious diseases. Manipulating T-cell functions provides a promising avenue for precision medicine. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a transcription factor regulating redox balance, has emerged as a suppressor of T-cell inflammation and anti-tumor responses. Our recent studies revealed that Nrf2 modulates T-cell expansion and metabolism, influencing immune responses. Our preliminary data showed that while Nrf2 activation in T-cells alleviated inflammatory bowel disease (IBD) disease pathology by suppressing inflammation, Nrf2 deficiency improved melanoma outcomes by boosting T-cell cytotoxicity. Thus, targeting Nrf2 in T-cells could serve as a strategy to fine-tune inflammatory and cytotoxic functions. This project aims to manipulate Nrf2 in T-cells using PROTAC technology to either suppress inflammation in inflammatory bowel disease (IBD) or enhance anti-tumor T-cell responses against melanoma. Instead of conventional Nrf2-targeting drugs with off-target effects, we propose using PROTACs, which offer higher specificity, potency, and prolonged inhibition. As Aim 1, we will develop Keap1-degrading PROTACs to activate Nrf2 in T-cells, suppressing inflammatory Th1 and Th17 cells while enhancing regulatory T-cells (Tregs) to alleviate IBD. The efficacy of these PROTACs in vivo will be tested in preclinical IBD models. As Aim 2, we will evaluate Nrf2-degrading PROTACs to enhance CD8+ T-cell-mediated anti-tumor responses. The efficacy of these PROTACs will be tested alone and in combination with checkpoint inhibitors in mouse models of melanoma. These studies will establish PROTAC-based strategies for precise immune modulation of T-cells and utilize them in different disease conditions.