Second, TOX removal enables Tex fate flexibility. However, given the requirement for i) TOX for Tex survival and ii) external cues to induce Tex rewiring, therapeutic TOX targeting must be combined with approaches that promote both cell survival and Teff differentiation

Notably, TOX removal endowed established Tex with greater flexibility. In the presence of Teff-driving signals, TOX iKO Tex partially converted into Teff-like cells and acquired greater cytokine-producing and tumor-killing capacities.

Indeed, gene expression and epigenetic profiling revealed a role for TOX in maintaining key cellular processes in Tex including mitochondrial function, along with Tex epigenetic programming underlying terminal differentiation and survival

Numerical loss of TOX iKO was reversed through opposing apoptosis via concurrent BIM and TOX targeting. However, “rescued” TOX iKO did not regain inhibitory receptor expression, suggesting that TOX preserves both Tex survival and ongoing Tex programming

Here, we identified TOX as a key epigenetic factor that preserves Tex biology. Induced TOX deletion in established Tex (TOX iKO) resulted in apoptosis-driven reduction in Tex number and loss of key Tex features (e.g., PD-1, terminal differentiation)