Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate

Although checkpoint blockade temporarily improves exhausted CD8 T (T_ex) cell function, the underlying T_ex epigenetic landscape remains largely unchanged, preventing durable T_ex "reinvigoration" in cancer and chronic infections. The transcription factor TOX initiates T_ex epigenetic programming, yet it remains unclear whether TOX continually preserves T_ex biology after T_ex establishment. Here, we demonstrated that induced TOX ablation in committed T_ex cells resulted in apoptotic-driven loss of T_ex cells, reduced expression of inhibitory receptors, and decreased terminal differentiation. Gene expression and epigenetic profiling revealed a critical role for TOX in maintaining chromatin accessibility and transcriptional patterns in committed T_ex cells. Moreover, TOX removal endows established T_ex cells with greater fate flexibility to differentiate into more functional effector-like T cells. Thus, continuous TOX expression in established T_ex cells acts as a durable epigenetic barrier reinforcing the T_ex developmental fate. TOX manipulation even after T_ex establishment could therefore provide therapeutic opportunities to rewire T_ex cells in chronic infections or cancer.