BACH2 dosing preserves T cell stemness without compromising effector functions, enhancing persistence and anti-tumour immunity
T cell therapies are poised to revolutionize treatment of solid cancers but efficacy is limited by poor maintenance of transferred cells. Previous strategies have relied on enforcing activated and potentially oncogenic states. Nonetheless, durable physiological T cell responses arise from stem-like progenitors and depend on the transcription factor BACH2. Here, we show that graded BACH2 expression governs the continuum between stem and effector CD8? T cells, enabling engineering of synthetic states with improved persistence and anti-tumor activity. While constitutively high BACH2 levels enforce quiescence and limit tumor control, low-dose BACH2 permits effector differentiation while retaining stem-like properties, resulting in enhanced therapeutic efficacy. Mechanistically, low-dose BACH2 partially restrains AP-1 enhancer occupancy in highly AP-1–dependent genes while sustaining effector programs. In addition, we also show this dosage principle generalizes to other quiescent factors such as FOXO1. Thus, quantitative tuning of quiescence factors emerges as a strategy to improve T cell immunotherapy.