Continuous expression of TOX safeguards exhausted CD8 T cell epigenetic fate.

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