Stat5 opposes the transcription factor Tox and rewires exhausted CD8+T cells toward durable effector-like states during chronic antigen exposure

Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a rocally antagonistic circuit between Stat5a and Tox. Stat5 directed Texint cell formation and re-instigated tial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with supe-rior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rb-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprog-rammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight thera-peutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.