Nrf2作为改善肌层浸润性膀胱癌（MIBC）中T细胞功能的治疗靶点

Introduction: Bladder cancer is the seventh most common malignancy in the United States, with an estimated 16,840 deaths in 2024. Despite advances in surgical management and chemotherapy, muscle invasive bladder cancer (MIBC) remains associated with poor survival outcomes. Only ~20% of MIBC patients show durable responses to immune checkpoint inhibitors. Thus, there remains a critical unmet need to understand the mechanisms of immune resistance within MIBC tumor microenvironment and to develop therapies that can enhance T cell functions to improve patient outcomes. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor, regulated by Kelch-like ECH-associated protein 1 (Keap1), which protects against oxidative stress. However, its role in modulating the immune microenvironment, particularly the T cells in MIBC, remains poorly understood. Recently, it was reported that Nrf2-mediated oxidative stress response pathway is upregulated in tumor-infiltrating T cells compared to circulating T cells in bladder cancer patients. We and others have reported that loss of Nrf2 in T cells elevates IFN-gamma and Granzyme B expression, supporting a cytotoxic phenotype, while Nrf2 activation exerts the opposite effect by repressing these key effector molecules. Based on these observations, we hypothesized Nrf2 inhibition will suppress MIBC progression by enhancing T cell-mediated anti-tumor immunity. Methods: We used mice with T cell-specific deletion of Nrf2 (Nrf2-KO) or constitutive activation of Nrf2 by deleting its negative regulator Keap1 (Keap1-KO) to evaluate the T cell-intrinsic role of Nrf2 in MIBC. In vivo , we assessed tumor growth of BBN963 cells in a syngeneic bladder cancer model. In vitro , we performed tumor-killing assays by coculturing CD8⁺ T cells, treated with the Nrf2 inhibitor ML385 and with BBN963 cells. Results: BBN963 tumors implanted in Nrf2-KO mice (with Nrf2-depleted T cells) exhibited remarkably reduced tumor growth compared to wildtype mice while Keap1-KO mice (elevated Nrf2 in T cells) displayed significantly larger tumors. Pharmacological inhibition of Nrf2 using ML385 improved the tumor-killing ability of CD8⁺ T cells against BBN963 bladder cancer cells in vitro . Conclusions: Together, these findings identify a previously unrecognized T cell intrinsic role of Nrf2 in suppressing antitumor immunity and promoting bladder cancer progression. Our work highlights Nrf2 as an immune checkpoint for T cells and indicates its targeting as a promising therapeutic strategy, especially in synergy with current immunotherapies, to improve MIBC patient outcomes.