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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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“Lynn found that c-Jun over-expression in CAR-T induces exhaustion resistance (28).”
BackgroundFüchsl, F., & Krackhardt, A. M. (2022) · Cancers · doi:10.3390/cancers14174192 · Cited by 9
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RetractedFunctional diversification and dynamics of CAR-T cells in patients with B-ALL
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Cheng, J., Zheng, J., Ma, C., Li, Y., & Hao, H. (2025) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2025.05.010 · Cited by 8
Pan-cancer analysis identifies CD155 as a promising target for CAR-T cell therapy
Liu, X., Sun, Y., Lin, B., Xiong, H., Lu, X., Tan, B., Zhang, C., Liu, M., Qin, J., Zhang, N., et al. (2025) · Genome Medicine · doi:10.1186/s13073-025-01490-0 · Cited by 8
“However, studies have indicated that excessive affinity and strong stimulatory signals lead to exhaustion of CAR-T cells [56], whereas lower affinity can enhance the persistence of CAR-T cells in vivo [57] .”
Enhancing the potency of CAR-T cells against solid tumors through transcription factor engineering
Chen, R., Chen, L., Tang, Y. R., Xiaolin, S., Wang, Y., Tang, P., Shentu, X., & Sun, J. (2025) · JCI Insight · doi:10.1172/jci.insight.193048 · Cited by 9
“Overexpression of c-Jun can reverse the dysfunction in exhausted HA-28z CAR-T cells, resulting in enhanced antitumor efficacy through elevated IL-2 and IFN-γ production, sustained proliferation, and increased fraction of Tscm and Tcm subsets (8).”
InfluentialSynthetic biology approaches to enhance cancer immune responses
Liu, S., Zhong, Z., Tu, Q., & Jin, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1698158 · Cited by 8
“Alternative strategies include the use of dominant-negative receptors or transient pharmacological checkpoint inhibition to achieve more controlled modulation of immune responses (53).”
Heard, A. D., Chang, J., Warrington, J. M., & Singh, N. (2021) · Best Practice & Research Clinical Haematology · doi:10.1016/j.beha.2021.101304 · Cited by 8
Wang, J., Shang, Z., Wang, J., Xu, J., Li, W., Guan, Y., Li, Y., Zhang, W., Shen, K., Zhang, M., et al. (2021) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2020-002029 · Cited by 8
“Furthermore, Lynn et al 18 found that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells which indicates that deficiency of crucial genes may extensively influence T cell function.”
Lamture, G., Baer, A., Fischer, J. W., Colon‐Moran, W., & Bhattarai, N. (2021) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000402 · Cited by 9
Flubendazole inhibits PD-1 and suppresses melanoma growth in immunocompetent mice
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“Interestingly, recent studies show that overexpression of JUN in T cells can reinvigorate T cells and improve anti-tumor potency [24].”
BackgroundApplications of single‐cell omics for chimeric antigen receptor T cell therapy
Ghaffari, S., Saleh, M., Akbari, B., Ramezani, F. M., & Mirzaei, H. R. (2023) · Immunology · doi:10.1111/imm.13720 · Cited by 8
“Subsequently, synthetic overexpression of c-Jun not only reduced exhaustion and increased long-term expansion capability, but also enhanced CAR T cells in vivo anti-tumour activity, offering new targets to address exhaustion [68].”
BackgroundInfluentialp38 Kinase: A Key Target for Driving Potent T Cells for Adoptive Immunotherapy
Chan, J. D., Beavis, P. A., & Darcy, P. K. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.05.012 · Cited by 8
An overview of multiplexed analyses of CAR T-cell therapies: insights and potential
DePriest, B. P., Vieira, N., Bidgoli, A., & Paczesny, S. (2021) · Expert Review of Proteomics · doi:10.1080/14789450.2021.1992276 · Cited by 9
“mechanisms of exhaustion include the AP-1 related bZIP-IRF families [112], NFAT/NR4A axis [113,114] and TOX transcription factor [115].”
BackgroundOvercoming CAR T cell exhaustion
Minton, K. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0265-x · Cited by 8
Peltier, D., Radosevich, M., Ravikumar, V., Pitchiaya, S., Decoville, T., Wood, S. C., Hou, G., Zajac, C. K., Oravecz-Wilson, K. I., Sokol, D., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.aaz0316 · Cited by 9
“In this scenario, we specifically postulate that T cell activation induces repressive AP-1 complexes (55, 56) that are recruited to these binding sites within the regulatory elements of Linc00402.”
BackgroundMcCutcheon, S. R., Swartz, A. M., Brown, M. C., Barrera, A., Amador, C. M., Siklenka, K., Humayun, L. L., Isaacs, J. M., Reddy, T. E., Nair, S. K., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.05.01.538906 · Cited by 8
Ong, S. Y., Chen, Y., Tan, M. S. Y., Ho, A. Y. L., Hwang, W. Y. K., & Lim, F. (2023) · European Journal Of Haematology · doi:10.1111/ejh.13964 · Cited by 7
“…that promote exhaustion 59,74 • Overexpress BATF, which regulates T cell subset specification away from T cell exhaustion lineage towards effector 75 • Disrupt transcriptional program by deleting SOX4 or ID3 76 • Disrupt epigenetic program that enforces exhaustion by deleting TET2, SUV39H1, or…”
BackgroundGeneration of CAR-TSCM: CAR-T with super clutch
Hu, J., & Liu, X. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112379 · Cited by 8
GD2 targeting CAR T cells for neuroblastoma
Anderson, J., Barone, G., & Zehner, A. (2024) · EJC Paediatric Oncology · doi:10.1016/j.ejcped.2024.100179 · Cited by 7
“In preclinical studies the Stanford group have demonstrated that the 14.18 scFv in a modified high affinity version is responsible for severe tonic signaling, and this results in reduced functionality of manufactured cell products compared with non-leaky binders [14 – 16].”
InfluentialJunB is required for CD8+ T cell responses to acute infections
Sarkar, S., Taira, N., Hsieh, T.-H., Chien, H.-C., Hirota, M., Koizumi, S.-I., Sasaki, D., Tamai, M., Seto, Y., Miyagi, M., et al. (2024) · International Immunology · doi:10.1093/intimm/dxae063 · Cited by 9
“An interesting question for future studies is whether JunB directly or indirectly modulates the expression or activity of NR4A1 and c-Jun, which promote and inhibit T cell exhaustion, respectively (58, 59).”
Optimising CAR T therapy for the treatment of solid tumors
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“Successful examples include the over-expression of c-jun [160], AKT [161], Bcl-2 [162,163], Bcl-xl [163] and oncogenic mutations associated with T cell malignancy [164].”
Xiong, S., Zhang, S., Yue, N., Cao, J., & Wu, C. (2025) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2025.2458214 · Cited by 7
“So modification of cAR-t cells to overexpress c-Jun renders them resistant to depletion, and engineered cAR-t cells overexpressing c-Jun were shown to decrease or replace the AP-1i on chromatin, thereby preventing t cell exhaustion [76].”
Wu, S., Wei, Y., Qiu, Y., Ai, K., Chen, M., Wang, H., Zhang, H., Cen, Q., Liao, P., Ding, X., et al. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-024-05907-z · Cited by 13
“Furthermore, the AP-1/bZIP family and NR4A transcription factors, which are the main drivers of exhaustion-related gene expression, indicate that c-Jun overexpression or NR4A deficiency can make CAR-T cells resistant to exhaustion [9, 10].”
Conn, B. P., Dietze, J. L., Yee, C. J., Hallisey, M., Ortiz-Caraveo, I., van Buuren, M. M., Gaynor, R. B., Foley, K. C., Choi, J., & Juneja, V. R. (2025) · Cell Reports Methods · doi:10.1016/j.crmeth.2025.101049 · Cited by 9
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“63 This strategy effectively counters chronic TCR signaling by reinforcing AP-1 – mediated transcription.”
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“An alternate strategy is the expression of positive signaling molecules such as C-Jun (Lynn et al, 2019) or runt-related transcription factor 3 (Tang et al, 2023; Zhu et al, 2023), or constitutively active cytokine receptors (Bell et al, 2023).”
Multimodal delineation of a layer of effector function among exhausted CD8 T cells in tumors
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“CAR T cells can also be ‘armed’ with cJun to prevent their exhaustion [14].”
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“Functionally deficient c‐ Jun promotes the exhaustion of CAR T‐cells, and CAR T‐cells overexpressing c‐Jun confers resistance to exhaustion.(68)”
Backgroundc-Met is a chimeric antigen receptor T-cell target for treating recurrent nasopharyngeal carcinoma
Huo, Q., Lv, J., Zhang, J., Huang, H., Hu, H., Zhao, Y., Zhang, X., Wang, Y., Zhou, Y., Qiu, J., et al. (2023) · Cytotherapy · doi:10.1016/j.jcyt.2023.06.004 · Cited by 7
“This might be due to Ab928zCAR induced T-cell self-activation and could lead to T-cell exhaustion, which is similar to anti-GD2 (14g2a-E101K) CAR-T cells with high affinity [44].”
BackgroundCorneal Sensory Nerve Injury Disrupts Lacrimal Gland Function by Altering Circadian Rhythms in Mice
Li, S., Xie, J., Xiang, J., Yan, R., Liu, J., Fan, Q., Lu, L., Wu, J., Liu, J., Xue, Y., et al. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.4.40 · Cited by 7
“31 Quality control of raw sequencing reads ensured high-quality clean data for down-stream analysis.”
SCAN-ACT: adoptive T cell therapy target discovery through single-cell transcriptomics
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Zhang, Y., Huang, M., Zhang, S., Liu, T., Ye, S., Cheng, Y., Cao, Y., Chen, L., Zhu, L., Sun, X., et al. (2025) · Experimental Hematology and Oncology · doi:10.1186/s40164-025-00701-z · Cited by 6
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Mariniello, A., & Migliorini, D. (2026) · iScience · doi:10.1016/j.isci.2025.114609 · Cited by 9
“113,114 Alternatively, a stem-like/memory phenotype is induced through metabolic changes, modulating the differentiation fate of T cells at the epigenetic level.”
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“JUN overexpression in CAR T cells has been shown to reduce terminal differentiation in mouse tumor models, 56 consistent with our observation that PB provides a more favorable environment for maintaining functional CAR T cells.”
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Warmuth, L., Dötsch, S., Trebo, M., Bellucci, S., Engels, S., Manrique, R. V., Moukarzel, K., Schütz, J. M., Hammel, M., Straub, A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-71354-7 · Cited by 8
“These issues can be partially attributed to the use of high-af fi nity receptors, which trigger supra-physiological activation of CAR-T cells favoring exhaustion 69 , enhancing the selection towards antigen loss and fratricide 28 , and contributing to more severe acute toxicities 25 .”
Uncovering receptor-ligand interactions using a high-avidity CRISPR activation screening platform
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“This study revealed that the levels of phospho- c-Jun (p- c-Jun), a transcription factor recently found to be critical for optimal CAR-T cell activation ( 43 ), decreased markedly in the presence of siglec-4 (fig.”
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“79,80 Endeavors have been made to mitigate exhaustion and revive exhausted CAR-T cells.”
BackgroundLei, K., Li, J., Tu, Z., Gong, C., Liu, J., Luo, M. H., Ai, W., Wu, L., Li, Y., Zhou, Z., et al. (2024) · Theranostics · doi:10.7150/thno.98574 · Cited by 6
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BackgroundLi, A. W., Briones, J. D., Lü, J., Walker, Q., Martinez, R., Hiraragi, H., Boldajipour, B. A., Sundar, P. D., Potluri, S., Lee, G., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-72392-1 · Cited by 6
“Many ongoing efforts exist to create more potent CAR T cells by genetically engineering T cells to express additional proteins (‘armored’ CAR T cells) 12,47, knock out specific genes 48,49 , or by including small-molecule agents within the T-cell production process 50,51 .”
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Correlative studies reveal factors contributing to successful CAR-T cell therapies in cancer
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“These features resulted in improved in vivo tumor control across several pre-clinical models [28].”
Library-based single-cell analysis of CAR signaling reveals drivers of in vivo persistence
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Aoyama, S., Yasuda, S., Li, H., Watanabe, D., Umezawa, Y., Okada, K., Nogami, A., Miura, O., & Kawamata, N. (2022) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2022.5097 · Cited by 6
“cAR‐T cells were established as previously reported (8,9).”
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“Recently, it has been demonstrated that overexpression of c-Jun is able to induce CAR T cells to acquire resistance to T cell exhaustion (Lynn et al., 2019).”
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Characterizing control of memory CD8 T cell differentiation by BTB-ZF transcription factor Zbtb20
Preiss, N. K., Kamal, Y., Wilkins, O. M., Li, C., Kolling, F., Trask, H. W., Usherwood, Y.-K., Cheng, C., Frost, H. R., & Usherwood, E. J. (2023) · Life Science Alliance · doi:10.26508/lsa.202201683 · Cited by 7
“In the setting of immunotherapy, chimeric antigen receptor (CAR) T cell exhaustion can be ameliorated by adjusting the dosage of particular AP-1 components, namely, cJun in a model of CAR T cell exhaustion (Lynn et al, 2019).”
Lu, X., Lofgren, S., Zhao, Y., & Mazur, P. K. (2023) · Nature Biomedical Engineering · doi:10.1038/s41551-023-01085-3 · Cited by 6
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Coopting T cell proximal signaling molecules enables Boolean logic-gated CAR T cell controlPreprint
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Lifespan‐Regulated CAR‐Macrophages from Myeloid Progenitors for Enhanced Colorectal Cancer Therapy
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“Ectopic expression of c-Jun improves persistence and antitumor activity of engineered human CAR-T and TCR-transgenic T cells by reducing T cell exhaustion 31,32 .”
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“Evaluation of a panel mutants de fi cient in transcriptional activation or chromatin binding ability revealed that the functional advantages conferred by c-Jun were at least partly mediated by displacement of AP-1 – IRF complexes from the chromatin, and not direct transcriptional effects (146).”
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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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