Alberto G. Conti, Alexander C. Evans, Teresa von Linde, Christian Deo T. Deguit, Sarah K. Whiteside, Alexander J. Wesolowski, Charlotte J. Imianowski, Yumi Yamashita-Kanemaru, Layla Dahmani, Jack Chapman, Ardon M. Pillay, Aws Al-Deka, RANDY GREAVES, Oliver T. Burton, Panagiota Vardaka, Shienny Sampurno, Iván Pérez-Núñez, Nicole Y. L. Saw, J. Yang, Andrew J. M. Howden, Klaus Okkenhaug, Suman Mitra, Bartłomiej Świątczak, Ian A. Parish, Rahul Roychoudhuri
Adoptive T cell therapies are limited by poor persistence of transferred cells. Attempts to enhance persistence have focused on genetic induction of constitutively hyperactivated but potentially oncogenic T cell states. Physiological T cell responses are maintained by quiescent stem-like/memory cells dependent upon the transcription factor BACH2. Here we show that quantitative control of BACH2 dosage regulates differentiation along the continuum of stem and effector CD8⁺ T cell states, enabling engineering of synthetic states with persistent antitumor activity. While conventional high-level overexpression of BACH2 enforces quiescence and hinders tumor control, low-dose BACH2 expression promotes persistence without compromising effector function, enhancing anticancer efficacy. Mechanistically, low-dose BACH2 partially attenuates Jun occupancy at highly AP-1-dependent genes, restraining terminal differentiation while preserving effector programs. Similarly, dose optimization enables effective deployment of quiescence factor FOXO1. Thus, quantitative control of gene payloads yields qualitative effects on outcome with implications for quiescence factor deployment in cell therapy.