Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

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 Burton; Panagiota Vardaka; Shienny Sampurno; Iván Pérez-Núñez; Nicole Y.L. Saw; Jie Yang; Andrew J.M. Howden; Klaus Okkenhaug; Suman Mitra; Bartlomiej Swiatczak; Ian A. Parish; Rahul Roychoudhuri

doi:10.1038/s41590-025-02389-z

Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

Alberto G. Conti (Lead / Corresponding author)
, Alexander C. Evans (Lead / Corresponding author)
, 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 Burton
, Panagiota Vardaka
, Shienny Sampurno
, Iván Pérez-Núñez
, Nicole Y.L. Saw
, Jie Yang
, Andrew J.M. Howden

Klaus Okkenhaug, Suman Mitra, Bartlomiej Swiatczak, Ian A. Parish, Rahul Roychoudhuri (Lead / Corresponding author)

Cell Signalling and Immunology

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English
Journal	Nature Immunology
Early online date	16 Jan 2026
DOIs	https://doi.org/10.1038/s41590-025-02389-z
Publication status	E-pub ahead of print - 16 Jan 2026

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Cite this

Conti, A. G., Evans, A. C., von Linde, T., Deguit, C. D. T., Whiteside, S. K., Wesolowski, A. J., Imianowski, C. J., Yamashita-Kanemaru, Y., Dahmani, L., Chapman, J., Pillay, A. M., Al-Deka, A., Greaves, R., Burton, O., Vardaka, P., Sampurno, S., Pérez-Núñez, I., Saw, N. Y. L., Yang, J., ... Roychoudhuri, R. (2026). Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy. Nature Immunology. Advance online publication. https://doi.org/10.1038/s41590-025-02389-z

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title = "Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy",

abstract = "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.",

author = "Conti, \{Alberto G.\} and Evans, \{Alexander C.\} and \{von Linde\}, Teresa and Deguit, \{Christian Deo T.\} and Whiteside, \{Sarah K.\} and Wesolowski, \{Alexander J.\} and Imianowski, \{Charlotte J.\} and Yumi Yamashita-Kanemaru and Layla Dahmani and Jack Chapman and Pillay, \{Ardon M.\} and Aws Al-Deka and Randy Greaves and Oliver Burton and Panagiota Vardaka and Shienny Sampurno and Iv{\'a}n P{\'e}rez-N{\'u}{\~n}ez and Saw, \{Nicole Y.L.\} and Jie Yang and Howden, \{Andrew J.M.\} and Klaus Okkenhaug and Suman Mitra and Bartlomiej Swiatczak and Parish, \{Ian A.\} and Rahul Roychoudhuri",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2026.",

year = "2026",

month = jan,

day = "16",

doi = "10.1038/s41590-025-02389-z",

language = "English",

journal = "Nature Immunology",

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Conti, AG, Evans, AC, von Linde, T, Deguit, CDT, Whiteside, SK, Wesolowski, AJ, Imianowski, CJ, Yamashita-Kanemaru, Y, Dahmani, L, Chapman, J, Pillay, AM, Al-Deka, A, Greaves, R, Burton, O, Vardaka, P, Sampurno, S, Pérez-Núñez, I, Saw, NYL, Yang, J, Howden, AJM, Okkenhaug, K, Mitra, S, Swiatczak, B, Parish, IA & Roychoudhuri, R 2026, 'Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy', Nature Immunology. https://doi.org/10.1038/s41590-025-02389-z

TY - JOUR

T1 - Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

AU - Conti, Alberto G.

AU - Evans, Alexander C.

AU - von Linde, Teresa

AU - Deguit, Christian Deo T.

AU - Whiteside, Sarah K.

AU - Wesolowski, Alexander J.

AU - Imianowski, Charlotte J.

AU - Yamashita-Kanemaru, Yumi

AU - Dahmani, Layla

AU - Chapman, Jack

AU - Pillay, Ardon M.

AU - Al-Deka, Aws

AU - Greaves, Randy

AU - Burton, Oliver

AU - Vardaka, Panagiota

AU - Sampurno, Shienny

AU - Pérez-Núñez, Iván

AU - Saw, Nicole Y.L.

AU - Yang, Jie

AU - Howden, Andrew J.M.

AU - Okkenhaug, Klaus

AU - Mitra, Suman

AU - Swiatczak, Bartlomiej

AU - Parish, Ian A.

AU - Roychoudhuri, Rahul

PY - 2026/1/16

Y1 - 2026/1/16

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105027755277

U2 - 10.1038/s41590-025-02389-z

DO - 10.1038/s41590-025-02389-z

M3 - Article

C2 - 41545541

AN - SCOPUS:105027755277

SN - 1529-2908

JO - Nature Immunology

JF - Nature Immunology

ER -

Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy

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