ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation
Progenitor CD8<sup>+</sup> T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8<sup>+</sup> T cell effector differentiation. ZFP148-deficient CD8<sup>+</sup> T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148<sup>fl/fl</sup> controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8<sup>+</sup> T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8<sup>+</sup> T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8<sup>+</sup> T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.
Authors
- No‐Joon Song (ORCID: https://orcid.org/0009-0002-0947-0597)
- Amir Yousif (ORCID: https://orcid.org/0000-0002-7300-1667)
- Dan Theodorescu (ORCID: https://orcid.org/0000-0002-8708-8206)
- Debasish Sundi (ORCID: https://orcid.org/0000-0001-6980-4777)
- Hazem E. Ghoneim (ORCID: https://orcid.org/0000-0002-9816-4286)
- Mark P. Rubinstein (ORCID: https://orcid.org/0000-0003-4748-0286)
- Payton Weltge (ORCID: https://orcid.org/0000-0001-9404-6744)
- Kenneth J. Oestreich (ORCID: https://orcid.org/0000-0002-3004-072X)
- Maria Velegraki (ORCID: https://orcid.org/0000-0003-3062-9777)
- Anjun Ma (ORCID: https://orcid.org/0000-0001-6269-398X)
- Heng-Yi Chen (ORCID: https://orcid.org/0000-0001-9283-6144)
- Tong Xiao (ORCID: https://orcid.org/0009-0007-7996-4134)
- J. A. Merchant
- R.S. Brown
- Fengxia Gao
- Z. Li
- Xingyu Chen
- Fang-Yun Lay
- Minh Quynh May Le
- Weiguo Cui
- Qin Ma
- Jay K. Mandula
- Xue Li
- Gang Xin
- Jianying Li
- Bella Weaver
- Yi Wang
- Chan-Wang Jerry Lio
Institutions
- Northwestern University (US)
- Cedars-Sinai Medical Center (US)
- University of Arizona (US)
- Medical College of Wisconsin (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- University of Arizona Cancer Center
- The Ohio State University (US)
Publication Details
- Journal
- Nature Immunology
- Published
- 2026-03-27
- DOI
- https://doi.org/10.1038/s41590-026-02461-2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00