Cytotoxic T lymphocytes (CTLs) play a crucial role in cancer rejection. However, CTLs encounter dysfunction and exhaustion in the immunosuppressive tumor microenvironment (TME). Although the reactive oxygen species (ROS)-rich TME attenuates the CTL function, the underlying molecular mechanism remains poorly understood. The nuclear factor-erythroid 2-related-2 (Nrf2) is ROS-responsible factor implicated in increasing susceptibility to cancer progression. Therefore, we examined how Nrf2 is involved in anti-tumor responses of CD8⁺ T and chimeric antigen receptor (CAR)-T cells under ROS-rich TME. Here, we demonstrated that tumor growth in Nrf2-/- mice was significantly controlled and was reversed by T cell depletion and further confirmed that Nrf2 deficiency in T cells promotes anti-tumor responses using adoptive transfer model of antigen-specific CD8⁺ T cells. Nrf2-deficient CTLs are resistant to ROS, and their effector functions are sustained in TME. Furthermore, Nrf2 knockdown in human CAR-T cells enhanced the survival and function of intratumoral CAR-T cells in solid tumor xenograft model and effectively controlled tumor growth. ROS-sensing Nrf2 inhibits the anti-tumor T cell responses, indicating that Nrf2 may be a potential target for T cell immunotherapy strategies against solid tumors.

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- Authors (Pusan National University): 

 · 1st author: Yuna Jo (Department of Anatomy and Department of Convergence Medical Science)

 · Corresponding author: Changwan Hong (Department of Anatomy and Department of Convergence Medical Science)

- Title of original paper: Targeting ROS-sensing Nrf2 potentiates anti-tumor immunity of intratumoral CD8⁺ T and CAR-T cells  

- Journal: Molecular Therapy

- DOI: https://doi.org/10.1016/j.ymthe.2024.08.019