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c-Jun overexpression in CAR T cells induces exhaustion resistance
Open accessAbstract
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer 1-3, but dysfunction due to T cell exhaustion is an important barrier to progress 4-6. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion 6. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells 7-10. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
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“T cell exhaustion also limits the efficacy of chimeric antigen receptor (CAR) T cell therapy against solid tumours14–17.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [14]
In the citing paper
“Next-generation T cell therapies are being engineered with transgenes designed to overcome suppressive signals in the tumor environment (Kloss et al., 2018; Lynn et al., 2019; Yamamoto et al., 2019).”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Lynn et al., 2019
In the citing paper
“c-Jun overexpression protects CAR-T cells from dysfunction by inducing T-cell exhaustion resistance [157].”
From Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases (2020) · cites this paper as [157]
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InfluentialLi, Y.-R., Nan, H., Liu, Z., Fang, Y., Zhu, Y., Lyu, Z., Shao, Z., Zhu, E., Zhang, B., Yang, Y., et al. (2026) · Nature Biomedical Engineering · doi:10.1038/s41551-026-01629-3 · Cited by 15
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“These cytokines, especially IFN(g) and IL2, are considered the hallmark metrics for measuring T-cell potency in the CAR-T field (18).”
BackgroundNaik, S., Velasquez, M. P., & Gottschalk, S. M. (2024) · Haematologica · doi:10.3324/haematol.2023.283817 · Cited by 15
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“Indeed, CAR-T cells induced to overexpress c-Jun resisted exhaustion thereby improving tumor clearance [156].”
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“5b, c), which is consistent with the expected functions of JUN mutants 63 .”
T-cell exhaustion in multiple myeloma
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“The authors identified AP-1-related bZIP/IRF families as major factors driving exhaustion-associated gene expression [80].”
BackgroundMyeloid cells meet CD8+ T cell exhaustion in cancer: What, why and how
Zhai, Y., Liang, X., & Deng, M. (2024) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2024.06.04 · Cited by 14
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New insights on potency assays from recent advances and discoveries in CAR T-cell therapy
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Transitioning from native to synthetic receptors: broadening T-cell engineering and beyond
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“Conversely, overexpression of BATF , c-JUN , or IRF4 enhances CD8 + T cell proliferation ( 11 , 65 , 66 ).”
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“Instead of adding a cell enrichment step to the CAR T cell manufacturing process, recent studies developed strategies to improve antitumor efficacy by CAR T cells through overexpressing signaling molecules that promote T cell stemness and/or repress exhaustion 6,34,35,45 .”
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“Intriguingly, it has recently been shown that forced expression of C-JUN can reverse the exhaustion phenotype in epigenetically exhausted/dysfunctional cells, highlighting the new therapeutic opportunities of manipulation of key transcriptional regulators [42].”
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“Lynn et al.(16) found that activator protein 1 (AP-1)/basic leucine zipper (bZIP) and bZIP/interferon regulatory factors (IRF) transcription factor (TF) binding motifs were highly enriched in exhausted CAR-T cells as a result of tonic signaling and showed that restoring the classic AP-1 heterodimer c-Fos/c-Jun by over…”
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“For instance, CAR-T cells engineered to overexpress a transcription factor c-Jun had an improved ability to resist exhaustion and maintain functionality despite prolonged activation [80].”
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Rafia, C., Harly, C., & Scotet, E. (2020) · Immunological Reviews · doi:10.1111/imr.12920 · Cited by 14
Yin, P., Yang, J.-G., Jiang, Y., Han, L., Xiong, T.-C., Liu, H., Fang, Y., Ruan, W., Wu, J., Chen, L., et al. (2025) · Science Advances · doi:10.1126/sciadv.adw3571 · Cited by 13
“…showed that NR4A3 KD CAR T cells during CAE displayed up-regulation of several AP-1 (bZIP) family members, including JUNB, JUND, BATF, and BATF3, which have been reported to drive an effector phenotype in T cells, enabling them to secrete large amounts of effector cytokines in tumors ( 30 , 32 ).”
InfluentialWu, Y., Wei, B., Wei, Z., Wang, H., Liu, Y., Xu, D., Li, X., Guo, L., Lu, H., & Shang, H. (2025) · Communications Biology · doi:10.1038/s42003-025-09310-2 · Cited by 13
“The AP-1 transcription factors were important for the cytotoxic lymphocyte development and antitumor immunity 18,19 , implying this subcluster of cells may play important roles in the TME.”
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“The prevailing view has been that tonic signalling is detrimental in CAR T cells as it leads to exhaustion and impairs anti-tumour activity [93,94].”
3D genomics and its applications in precision medicine
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“Although related progress has been amazing in recent years, research on 4D nucleosomes is still at the tip of the iceberg [127].”
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Shen, X., Zhang, R., Nie, X., Yang, Y., Hua, Y., & Lü, P. (2023) · Cancer Biotherapy and Radiopharmaceuticals · doi:10.1089/cbr.2023.0022 · Cited by 13
“Additionally, a previous study 38,101–104 has shown that T cell exhaustion is a significant issue with the use of the CD28 costimulation domain for CARs.”
Lee, H. J., Hwang, S. J., Jeong, E. H., & Chang, M. H. (2024) · The Journal of Microbiology · doi:10.1007/s12275-024-00133-0 · Cited by 13
“…to treat incurable diseases, which is related to methods to improve the TME and overcome antigen heterogeneity (Ghartey-Kwansah et al., 2018; Lynn et al., 2019; Rafiq et al., 2020; Xu et al., 2018). addition, the synthetic CAR-T cell technology we developed will establish the basic…”
BackgroundHan, L., Sun, X., Kong, J., Li, J., Feng, K., Bai, Y., Wang, X., Zhu, Z., Yang, F., Chen, Q., et al. (2024) · Journal of Translational Medicine · doi:10.1186/s12967-024-05577-x · Cited by 13
“The findings of our study demonstrated the upregulation of JUN in T cells derived from patients with aGVHD, suggesting a potential mechanism by which these T cells evade exhaustion by outcompeting exhaustion-inducing immunoregulatory transcription factors [67].”
ResultCAR T-cell therapy for B-cell lymphomas: outcomes and resistance mechanisms
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“…can be reversed or reduced through changes in the manufacturing conditions [45], immune checkpoint inhibitor therapy [29], increased stimulation through co-stimulatory molecules [46], targeting molecular pathways that lead to exhaustion [47–51], or by altering the signaling strength [26, 52–54].”
Sek, K., Chen, A. X. Y., Cole, T., Armitage, J. D., Tong, J., Yap, K. M., Munoz, I., Dunbar, P. A., Wu, S., van Elsas, M. J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59021-9 · Cited by 17
“Others have targeted factors that drive or prevent exhaustion such as c-Jun 57 , c-Myb 80 or BATF 44 .”
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“Ectopic c-Jun expression renders CAR-T cells exhaustion-resistant, enhancing their proliferation and IL-2/IFN γ production, leading to superior anti-tumor activity in murine leukemia models [164,165].”
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“JUN Expression Improved IL-2 production; Escaping T cell exhaustion [99]”
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“The Nalm6 cell line, which naturally expresses CD19 and CD22, is also widely used for in vitro experiments and in vivo mouse models in preclinical studies of B-cell malignancies [33, 34].”
BackgroundNiu, Q., Zhang, H., Wang, F., Xu, X., Luo, Y., He, B., Shi, M., Jiang, E., & Feng, X. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.03.033 · Cited by 12
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Mavuluri, J., Dhungana, Y., Jones, L. L., Bhatara, S., Shi, H., Yang, X., Lim, S.-E., Reyes, N., Chi, H., Yu, J., et al. (2025) · Cancer Discovery · doi:10.1158/2159-8290.cd-24-0841 · Cited by 11
“Manipula-tions diminishing exhaustion and enhancing CAR T-cell memory can increase CAR T-cell effectiveness (6–8).”
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Metadata
- Authors
- Lynn, R. C., Weber, E. W., Sotillo, E., Gennert, D., Xu, P., Good, Z., Anbunathan, H., Lattin, J., Jones, R., Tieu, V., Nagaraja, S., Granja, J., de Bourcy, C. F. A., Majzner, R., Satpathy, A. T., Quake, S. R., Monje, M., Chang, H. Y., & Mackall, C. L.
- Affiliations
- Lyell Immunopharma (United States) (US)
- Stanford Medicine (US)
- Stanford University (US)
- Parker Institute for Cancer Immunotherapy (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mackall, Crystal L.
- ORCID
- Venue
- Nature
- Published
- 2019-12-04
- Volume
- 576
- Issue
- 7786
- Pages
- 293-300
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6944329
- OpenAlex
- W2992738455
- Cited by
- 891
- References
- 63
- Citations by year
- 2026: 141 · 2025: 151 · 2024: 138 · 2023: 129 · 2022: 122 · 2021: 119 · 2020: 89 · 2019: 1
- FWCI
- 34.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (1s10od018220-01)
- National Human Genome Research Institute (RM1HG007735, P50HG007735)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- c-Jun, chimeric antigen receptor T cells, T cell exhaustion, AP-1 transcription factor, IL-2 deficiency, chromatin accessibility, IRF transcription factors, bZIP transcription factors, T cell expansion, antitumor immunity, CAR-T cell engineering
- MeSH terms
- Animals, Gene Expression Regulation, Humans, Neoplasms, Receptors, Antigen, T-Cell, Transcription, Genetic, Proto-Oncogene Proteins c-jun, Transcription Factor AP-1, Epigenesis, Genetic, Cell Line, Tumor, Mice
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