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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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Additional file 2 of Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers
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Additional file 5 of Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers
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Additional file 3 of Contextual reprogramming of CAR-T cells for treatment of HER2+ cancers
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Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection
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Kim, D., Park, J., Kang, M.-S., & Jung, H.-W. (2026) · Interdisciplinary Research in Medical Sciences Specialty · doi:10.51847/sliihvvjvi
In vivo CAR‑T therapy: recent progress and future directions
Wang, W., Cai, Y., Yang, X., & Xu, H. (2026) · Immunity & Inflammation · doi:10.1007/s44466-026-00050-4
“A parallel approach involves the co-delivery of anti-exhaustion genes, such as c-Jun [138] or FOXO1 [139, 140], which maintain CAR-T fitness in ex vivo settings.”
CAR‐Engineered Cell Therapies Beyond Cancer: Reprogramming Fibrosis and Immune‐Mediated Inflammation
Xu, P. J., Zhang, Z. J., Jin, J., Xu, H. Y., Gu, Y. X., Yang, Q. Q., & Zhou, Y. L. (2026) · Advanced Science · doi:10.1002/advs.77503
Self-citationDecoding T cell exhaustion in the tumour microenvironment
Park, J. A., Im, J., & Hwang, S.-M. (2026) · Experimental & Molecular Medicine · doi:10.1038/s12276-026-01809-w · Cited by 2
“This reprogramming enhances IL-2 production and improves anti-tumour activity in solid tumour models such as HER2 + osteosarcoma 104 .”
InfluentialMarei, H. E. S., Pozzoli, G., Caratelli, S., & Cenciarelli, C. (2026) · Stem Cell Research & Therapy · doi:10.1186/s13287-026-05266-0
Nakamura, N., Seo, H., Hamada, R., Kaneko, H., Kagoya, Y., & Ohta, S. (2026) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2026.154569
Ismail, M., Al‐Gizey, N., Alabed, Z., Mustafa, N., Al-Najjar, E., Hamdaneh, Y., Eid, N., & Esmail, A. (2026) · Pharmaceuticals · doi:10.3390/ph19091449
“Lynn et al. demonstrated that c-Jun-engineered CAR-T cells exhibited greater expansion, reduced terminal differentiation, and enhanced antitumor activity across multiple tumor models by displacing exhaustion-associated bZIP/IRF transcription factors from AP-1 binding sites [161].”
Beyond CAR-T: Preventing and Treating Relapse in B-Cell Haematological Malignancies
Canichella, M., Abruzzese, E., Cefalo, M., Gianfelici, V., Mazzone, C., Trotta, G. E., Laureana, R., Cupelli, L., & Principe, M. I. D. (2026) · Cells · doi:10.3390/cells15181660
“Synthetic biology approaches, including logic-gated CARs such as AND-and OR-gate circuits, may enable more selective recognition of malignant cells, while armored CARs and other engineered constructs may modify the tumor microenvironment [99–101].”
Machine learning–driven decoding of maternal immune signatures in repeated pregnancy loss
Ko, T. L., Park, J., Leem, D., Kim, J., Han, J. W., Park, J. S., Lee, S. K., & Paik, H. (2026) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1014806
Wang, K., Yu, L., Liang, X., Song, F., 江松福, Han, S., Zhang, M., Liu, K., Wen, R., Jin, L., et al. (2026) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2026-015196
“37 In line with their study, blinatumomab-elicited T cells in our results showed more exhausted phenotypes with lower expression of JUN and JUNB.”
Curtis, B. C., Spurrell, C. H., Flint, L., Lande, A. M., Leonardi, M., Rosser, J. M., Parker, T., Chai, T., Valdez, A., Toumi, R., et al. (2026) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2026.103117 · Cited by 1
Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases
Fan, Z., Zheng, X., Jin, C., Zhang, J., Gong, N., & Li, X. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02783-5
From failure to fate: Pressure-driven exhaustion in solid-tumor CAR T-cell therapy
Wang, P., Zhou, Y., Wang, Y., Li, Y., Xiao, X., & Wang, C. (2026) · Cell Insight · doi:10.1016/j.cellin.2026.100377
“Consistent with this model, insufficient AP-1 activity limits productive CAR T-cell function, whereas c-Jun reinforcement improves resistance to exhaustion (Lynn et al., 2019).”
InfluentialWhy only 3 months? Immunological constraints on CAR-T therapy in gastrointestinal cancers
Zeng, L., Wei, S., Chen, N., & Xie, X. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1942381
Tharuka, M. D. N., Chen, D.-H., Amaral, M. L. J., Ren, T., Kuang, Y., Huang, S., Chilakapati, N., Ren, B., Schoenberger, S. P., Zheng, Y., et al. (2026) · Science Advances · doi:10.1126/sciadv.aef2217
Toward the next generation of CAR T cell therapies for cancer
Usta, D., & Mackall, C. L. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.09.005
Self-citationLiu, W., Pan, X., Zhao, Y., Li, Z., Wu, D., & Liang, Y. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1890189
“…induces memory transcriptional programs and enhances CAR T-cell persistence (152, 153); c-Jun overexpression induces exhaustion resistance (154); NR4A knockout enhances memory potential (111); BATF and IRF4 cooperate to counteract exhaustion (119); and BLIMP1 and NR4A3 bidirectionally…”
Bunk, P., Ergin, I., Maher, T., Shah, V., Bonney, J. R., Kumar, L. B. S. S., Chung, C., Wellhausen, N., Moresco, P., Shao, S., et al. (2026) · Nature Immunology · doi:10.1038/s41590-026-02685-2
“Because CAR-T cell efficacy in solid tumors is limited by poor persistence, dysfunction and metabolic stress 43 , we next asked whether the PPARδ fitness program could translate to human cellular immunotherapy.”
InfluentialNoncanonical CD11b on CD8 + T cells promotes cytotoxic effector functionPreprint
de Durana, J. E.-D., Bosch, A., Prieto‐Fernández, E., Pérez, L., Yu, K., Velasco-Beltrán, P., Egia‐Mendikute, L., Oyenarte, I., Lee, S. Y., de Blas, A., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.10.07.757268
The tumor targetome in CAR-T and TCR-T cell therapy
Wang, S., Sun, B., Rai, S., Yang, X., Banday, S., Memon, A., Kearl, T., Hematti, P., Shah, N., Dong, J., et al. (2026) · Targetome · doi:10.48130/targetome-0026-0050
CAR-T-centered sequential therapy: current status, challenges, and future clinical perspectives
Zhou, L., Tian, C., Du, R., Chen, Y., Xu, Z., Wang, S., Chen, X., Zhang, H., Wang, Q., Cai, Q., et al. (2026) · Journal of Hematology & Oncology · doi:10.1186/s13045-026-01855-x
“Through overexpression of c-Jun, CAR-T cells can be rendered more resistant to exhaustion [101].”
Vo, M.-C., Kim, S. K., Bae, W. K., Ruzimurodov, N., Jung, S.-H., & Lee, J.-J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1983828
Next‐Generation CAR‐T Cell Therapy: From Modular Design to Clinical Expansion
Bai, Y.-S., Qin, J.-T., Dai, Z.-J., Yan, R., Yang, Y., & Wang, W.-G. (2026) · Exploration · doi:10.1002/exp2.70230
“In 2019, Lynn et al. demonstrated that over-expression of c-Jun suppressed the exhaustion program, enabling CAR-T cells to maintain high IFN-γ levels during long-term proliferation [ 69 ].”
Leng, X., & Hu, T. (2026) · The Innovation Oncology · doi:10.59717/j.xinn-oncol.2026.100033
Peripheral immune tolerance as a driver of tumor immune escape and therapy resistance
Vaishnave, S., Jayaraj, A., Selvaraj, J., Ramachandiran, S., Natarajan, M., Gunasekaran, B., & Lokaiah, T. (2026) · Clinical & Translational Oncology · doi:10.1007/s12094-026-04590-4
Molecular mechanisms regulating T-cell receptor signaling and T-cell function
Kurilin, V. V., Fisher, M. S., & Vitalievitch, S. S. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.2002535
“An optimal system should combine sensitivity to low target-antigen density with preserved speci fi city, controlled proximal-signal amplitude, resilience to repeated stimulation, and suf fi cient proliferative reserve (44, 52, 88, 92 – 100, 123, 125, 132, 133).”
From dysfunction to differentiation: a new paradigm of T cell exhaustion
Stepanova, V. M., Logvinov, A., Emelyanov, E. A., Katin, N. A., & Rubtsov, Y. P. (2026) · Acta Naturae · doi:10.32607/actanaturae.27873
“Similar results were reported for the overexpression of c-Jun, a transcriptional partner of BATF and IRF4, in human CAR-T cells [86].”
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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