The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Subramanian, A., Tamayo, P., Mootha, V. K., Mukherjee, S., Ebert, B. L., Gillette, M. A., Paulovich, A., Pomeroy, S. L., Golub, T. R., Lander, E. S., et al. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506580102 · Cited by 53,625
Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
ggplot2: Elegant Graphics for Data Analysis
Wickham, H. (2009) · doi:10.1007/978-0-387-98141-3 · Cited by 14,447
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkn923 · Cited by 14,108
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174
NCBI GEO: archive for functional genomics data sets—update
Barrett, T., Wilhite, S. E., Ledoux, P., Evangelista, C., Kim, I. F., Tomashevsky, M., Marshall, K. A., Phillippy, K. H., Sherman, P. M., Holko, M., et al. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks1193 · Cited by 10,418
Mootha, V. K., Lindgren, C. M., Eriksson, K.-F., Subramanian, A., Sihag, S., Lehar, J., Puigserver, P., Carlsson, E., Ridderstråle, M., Laurila, E., et al. (2003) · Nature Genetics · doi:10.1038/ng1180 · Cited by 10,197
Massively parallel digital transcriptional profiling of single cells
Zheng, G. X. Y., Terry, J. M., Belgrader, P., Ryvkin, P., Bent, Z. W., Wilson, R., Ziraldo, S. B., Wheeler, T. D., McDermott, G. P., Zhu, J., et al. (2017) · Nature Communications · doi:10.1038/ncomms14049 · Cited by 7,353 · cited 1×
“The cell-gene matrix was further processed using the Cell Ranger R Kit software (10X Genomics) as described 57 .”
Cited by
Sorted by citations
Items 601–700 of 897
Snyder, A. J., Garrison, S. M., Kluesner, M. G., Nutt, W. S., Shasha, C., Ho, T. T. G., Marsh, S. A., Linde, M. H., Wu, F., Meyer, L. K., et al. (2026) · Science Immunology · doi:10.1126/sciimmunol.adw7685 · Cited by 6
In vivo CAR-T therapy: from molecular design to precision delivery
Li, H., Wen, W., Zhao, X., & Liang, G. (2026) · Journal of Nanobiotechnology · doi:10.1186/s12951-026-04232-5 · Cited by 4
Rana, M. S., Fernandez‐Pol, S., Jensen, A. M., Hovanky, V. N., Velayati, A., Oak, J. S., Silva, O., Ames, E., Muffly, L. S., Sahaf, B., et al. (2026) · Blood Cancer Journal · doi:10.1038/s41408-026-01474-2 · Cited by 5
Self-citationCell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis
Bjelajac, J. R., Cañellas-Socias, A., Nehra, P., Reynolds, K., Malipatlolla, M. B., Martínez-Vélez, N., Manjarrez, D. C., Ho, K., Xu, P., Hamad, J. L., et al. (2026) · Cell · doi:10.1016/j.cell.2026.04.037 · Cited by 6
Self-citationMiltefosine reinvigorates exhausted T cells by targeting their bioenergetic state
Zhang, X., Zhang, C., Lu, S., Dong, J., Tang, N., Wang, Y., Han, W., Pan, X., Zhang, X., Liu, D., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101869 · Cited by 4
Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy
Chen, Z., & Zhou, X. (2025) · Acta Biochimica et Biophysica Sinica · doi:10.3724/abbs.2025190 · Cited by 6
“T cells engineered to overexpress the canonical AP - 1 factor c - Jun have increased expansion potential, increased functional capacity, diminished terminal differentiation, and improved anti - tumor potency in vivo [219].”
Liao, Q., Mao, Y., Feng, M., Zheng, N., Ding, X., Zhang, X., Wang, Z., & Xu, J. (2025) · Clinical Cancer Bulletin · doi:10.1007/s44272-025-00050-2 · Cited by 6
“One promising approach involves the overexpression of c-Jun in CAR-T cells, which enhances their expansion potential, functional capacity, and anti-tumor potency by counteracting the transcriptional programs associated with exhaustion [48].”
Newnes, H. V., Armitage, J. D., Audsley, K. M., Bosco, A., & Waithman, J. C. (2021) · Cancers · doi:10.3390/cancers13235911 · Cited by 5
“Further studies integrating single-cell protein, epigenetic and transcriptomic information have highlighted novel molecular factors that drive longterm persistence and efficacy of CAR-T cells in vivo [8,163].”
BackgroundEngineering cell-based therapies
Blazquez-Roman, J. L., Pisani, M., & Siciliano, V. (2022) · Elsevier eBooks · doi:10.1016/b978-0-12-824469-2.00023-3 · Cited by 4
Fine-tuning CARs for best performance
Hotblack, A., & Straathof, K. C. M. (2022) · Cancer Cell · doi:10.1016/j.ccell.2021.12.010 · Cited by 4
Zhang, Z., Qiu, X., Ning, H., Huang, Z., Tao, M., Liang, M., & Xie, Z. (2025) · Quantitative Biology · doi:10.1002/qub2.97 · Cited by 4
“Recent studies have revealed key transcription factors, including NFAT [7], IRF4 [8], c ‐ Jun [9], TOX [10, 11], and NR4A1 [12], that orchestrate exhaustion ‐ specific gene expression through complex epigenetic modifications.”
T Cell Exhaustion in Allergic Diseases and Allergen Immunotherapy: A Novel Biomarker?
Xu, Q., Li, L., & Zhu, R. (2025) · Current Allergy and Asthma Reports · doi:10.1007/s11882-025-01199-5 · Cited by 7
“Overexpression of c-Jun enhances the activity of exhausted CAR-T cells [113], while depleting Cbl-b suppresses CAR T cell exhaustion [114].”
The road ahead for chimeric antigen receptor T cells
Stewart, C. M., Siegler, E. L., & Kenderian, S. S. (2025) · The Journal of Immunology · doi:10.1093/jimmun/vkaf047 · Cited by 4
Prevention of CAR-T-cell dysfunction
LaFleur, M. W., Miller, B. C., & Sharpe, A. H. (2020) · Nature Biomedical Engineering · doi:10.1038/s41551-019-0512-2 · Cited by 4
Deng, L., Yu, X., Wu, Q. V., Song, X., Li, W., Hou, Y., Liu, Y., Wang, J., Tian, J., Zuo, X., et al. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1039929 · Cited by 4
Schultz, L. M., & Mackall, C. L. (2023) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2023.2227086 · Cited by 4
Self-citationModified T cells as therapeutic agents
Singh, N. (2021) · Hematology · doi:10.1182/hematology.2021000262 · Cited by 5
Engineered CD47 protects T cells for enhanced antitumor immunityPreprint
Yamada‐Hunter, S. A., Theruvath, J. L., McIntosh, B. J., Freitas, K. A., Radosevich, M., Leruste, A., Dhingra, S., Martínez-Vélez, N., Xu, P., Delaidelli, A., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.06.20.545790 · Cited by 4
Self-citationRestricting CAR T Cell Trafficking Expands Targetable Antigen SpacePreprint
Morales, E., Dietze, K. A., Baker, J. M., Wang, A., Avila, S. V., Cardenas, F. I., Radhakrishnan, S. V., Mause, E. R. V., Olson, M., Sun, W., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.02.08.579002 · Cited by 4
Harrer, D. C., Schlierkamp-Voosen, T., Barden, M., Pan, H., Xydia, M., Herr, W., Dörrie, J., Schaft, N., & Abken, H. (2025) · Cells · doi:10.3390/cells14120901 · Cited by 3
Yu, M., Yang, T., Ding, S., & Hu, Y. (2025) · American Journal of Hematology · doi:10.1002/ajh.70131 · Cited by 3
Rankin, A. W., Pham‐Danis, C., Novak, A. J., Danis, E. P., Fry, T. J., & Kohler, M. E. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011971 · Cited by 3
Chimeric antigen receptor-based cellular therapy for T-cell malignancies
Li, S., Li, Y., Hui, M. Y., Rashid, A., Tan, H. K., Chan, S., Chan, W. Y. K., Lam, K. S., Tu, W., & Leung, W. H. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.105044 · Cited by 3
CAR-T cell exhaustion in B cell lymphoma: Current status, mechanisms, and potential solutions
Zhao, R., Xia, J., Zheng, Y., Huang, W., Yu, L., & Wang, L. (2025) · Molecular Therapy Oncology · doi:10.1016/j.omton.2025.201099 · Cited by 3
“99 Hyungseok et al. found that overexpression of BATF in CD8+ T cells expressing a CAR promoted the survival and expansion of tumor-infiltrating CAR-T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription…”
The race between 4-1BB- and CD28-based CD19 CAR-T products in the therapy of B-cell malignancies
Krawczyk, M., Drużyńska, M., Bednarska, E., & Winiarska, M. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189519 · Cited by 4
The LXRβ/NF-κB axis reprograms CAR-T cells to resist exhaustion in the tumor microenvironment
Lim, M., Jung, S.-E., Koh, C., Jeong, H., Moon, Y. W., & Seo, H. (2026) · OncoImmunology · doi:10.1080/2162402x.2025.2611615 · Cited by 3
“This places RelB among transcription factors such as NR4A, BATF, and NFAT, which regulate exhaustion 11,29,30 but with a unique role in LXRβ-linked programs.”
Balke‐Want, H., Keerthi, V., Arenas, M. D. C., Chen, Y., Malipatlolla, M. B., Klysz, D. D., Xu, P., Ho, K., Asano, K., Stahl, D. J., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102549 · Cited by 3
“We have recently shown that c-JUN overexpression renders CAR T cells resistant against exhaustion, a dysfunctional cell state commonly observed in T cells targeting solid tumors, 46 and that c-JUN overexpression can overcome antigen heterogeneity.”
Self-citationCAR-T cell immunotherapy of malignant melanoma
Kharasakhal, O., & Maher, J. F. (2026) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2026.2621811 · Cited by 3
“;) constitutively active IL-7 receptor [145], oncogenes (e.g. c-jun c-jun [146], T-cell oncogenes [147]), anti-apoptotic Bcl2 family members [148,149], or dominant negative TGF-b receptors [150].”
Alli, R., & Youngblood, B. (2026) · Nature Immunology · doi:10.1038/s41590-026-02443-4 · Cited by 3
Wo, Y., Lu, T., Yang, Z., Li, X., Wang, Z., Peng, Y., Shen, X., Hou, F., Jiao, W., & Sun, Y. (2026) · Experimental Hematology and Oncology · doi:10.1186/s40164-026-00748-6 · Cited by 4
“Noteworthily, FOS and JUN were experimentally validated as master regulators of terminal differentiation and functional capacity of T lymphocytes [56, 57], and GADD45B was crucial for activating anti-tumor potency of T lymphocytes by upregulating IFN-γ expression [58].”
Hu, C., Zhang, H., Zhu, H., Fan, J., Chen, D., Zhu, S., Li, C., Sun, J., Chen, Y., Ren, J., et al. (2026) · Cell Death and Disease · doi:10.1038/s41419-026-08656-7 · Cited by 3
T cell exhaustion landscapes and therapeutic modulation in cancer immunity
Bautista, J., & López‐Cortés, A. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1827716 · Cited by 5
“…intrinsic regulatory bottlenecks rather than simply amplifying receptor engagement; for example, augmenting AP-1 activity has improved expansion and function in tonic-signaling CAR models, although such approaches remain bounded by toxicity considerations (Lynn et al., 2019; Chen et al., 2019).”
Cao, J.-Z., zhao, W., & Xia, X. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01811-y · Cited by 3
Hallmarks and correlates of effective adoptive cell immunotherapy for cancer
Krishna, S., Robbins, P. F., Lowery, F. J., & Rosenberg, S. A. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01312-3 · Cited by 4
Genome Engineering for Next-Generation Cellular Immunotherapies
Park, J. J.-Y., Lee, K. A. V., Lam, S. Z., Tang, K., & Chen, S. (2022) · Biochemistry · doi:10.1021/acs.biochem.2c00340 · Cited by 4
Sima, H., & Shao, W. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.113166 · Cited by 3
Interplay between CD28 and PD-1 in T cell immunotherapy
Jafri, Z., Zhang, J., O’Meara, C. H., Joshua, A. M., Parish, C. R., & Khachigian, L. M. (2024) · Vascular Pharmacology · doi:10.1016/j.vph.2024.107461 · Cited by 5
Motallebnejad, P., Lee, Z., One, J., Cichocki, F. M., Hu, W., & Azarin, S. M. (2025) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10747 · Cited by 3
“64,65 The STAT family also exhibited a significant increase in footprint depth and TFBM accessibility.”
Challenges facing CAR T-cell immunotherapy in multiple myeloma
Ouyang, W., & Mi, J. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104803 · Cited by 3
Multiplex engineering and multifunction T cells for precise and effective immunotherapies
Jafarzadeh, L., Smaani, A., & Delisle, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1680410 · Cited by 3
Une piste en immunothérapie du cancer
Bernard, P.-L., Laletin, V., Pastor, S., Nunès, J. A., & Guittard, G. C. (2020) · médecine/sciences · doi:10.1051/medsci/2020195 · Cited by 3
CAR T cells: from tinkering to rational design
MALISSEN, B. (2020) · Cell Research · doi:10.1038/s41422-020-00420-6 · Cited by 3
Temporal regulation of transgene expression controlled by amino acid availability in human T cells
Dougé, A., Vituret, C., Carraro, V., Parry, L., Coudy‐Gandilhon, C., Lemal, R., Combaret, L., Maurin, A., Averous, J., Jousse, C., et al. (2023) · HLA · doi:10.1111/tan.15252 · Cited by 3
Temporal regulation of transgene expression controlled by amino acid availability in human T cells
Dougé, A., Rouzaire, P., & Bruhat, A. (2023) · HAL · Cited by 3
Simulating the Evolution of Signaling Signatures During CART-Cell and Tumor Cell Interactions
Shah, V., Womack, J. A., Zamora, A. E., Terhune, S. S., & Dash, R. K. (2023) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) · doi:10.1109/embc40787.2023.10340076 · Cited by 3
Developing CAR T-Cell Therapies for Pediatric Solid Tumors
Canciani, G., Fabozzi, F., Pinacchio, C., Ceccarelli, M., & Bufalo, F. D. (2024) · Pediatric Drugs · doi:10.1007/s40272-024-00653-7 · Cited by 3
“…and colleagues significantly lowered the antigen density requirement of GPC2-CAR T cells in murine models of metastatic NB by incorporating the CD28-TM in the CAR and by inducing the overexpression of c-jun, a transcriptional factor related to T-cell activation and exhaustion resistance [57, 67].”
Not So FASt: Tumor Cells Resisting Death Drive CAR T-cell Dysfunction
Green, M. R., & Neelapu, S. S. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0037 · Cited by 3
“And can the resistance to death receptor–mediated killing be overcome by preventing exhaustion of CAR T cells through overexpression of JUN (8) or by enhancing their function and persistence by deletion of REGNASE1 (9) or PTPN2 (10)?”
BackgroundCAR-T cells for pediatric brain tumors: Present and future
Leruste, A., Beccaria, K., & Doz, F. (2021) · Bulletin du Cancer · doi:10.1016/j.bulcan.2021.06.002 · Cited by 3
Leveraging microRNAs for cellular therapy
Hasiuk, M., Dölz, M., Marone, R., & Jeker, L. T. (2023) · Immunology Letters · doi:10.1016/j.imlet.2023.08.005 · Cited by 3
Theruvath, J. L., Menard, M. J., Smith, B. A. H., Linde, M. H., Coles, G. L., Wu, W. E., Kiru, L., Delaidelli, A., Silberstein, J. L., Banuelos, A. M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.03.19.436221 · Cited by 3
Self-citationYu, P., Wei, H., Zhu, S., Li, J., Chen, C., Zhang, D., Li, Y., Zhu, L., Yi, X., Liu, N., et al. (2022) · Research Square · doi:10.21203/rs.3.rs-1989788/v1 · Cited by 3
Role of Flavonoids in Sepsis: Advances and Future ProspectsPreprint
Esmail, S. O., & Sahlan, A. Z. (2024) · Preprints.org · doi:10.20944/preprints202405.1306.v1 · Cited by 2
Rab5 Overcomes CAR T Cell Dysfunction Induced by Tumor-Mediated CAR CapturePreprint
Gu, M., Carvalho, E. J., Read, K. A., Nardo, D., & Riley, J. L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.07.26.605334 · Cited by 3
Caffeine-regulated molecular switches for functional control of CAR T cells in vivoPreprint
Sylvander, E., Salzer, B., Emminger, D., Baik, H., D’Accardio, G., Schäfer, M., Mouratidis, K., Buri, M. C., Maresch, D., Urbanetz, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.13.659487 · Cited by 3
“Importantly, these safety concerns are even increased with next generation CAR T cells that are additionally engineered to enhance potency and/or persistence, for example by overexpressing the AP-1 factor c-Jun 11 or disruption of TET2 12 .”
Transcription factor collaboration enables precise T cell state engineeringPreprint
Savage, R. E., Amador, C. D. M., Hock, C., Zhang, R., Kuo, H., Gao, A., Horlbeck, M. A., Gersbach, C. A., & Buenrostro, J. D. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.20.718569 · Cited by 5
“Single-cell atlases have defined diverse CD8 + T cell states across health and disease 18 and gain-and loss-of-function studies have nominated factors capable of shifting cells between these states 8–10 , 19– 23 .”
Kubick, N., Łazarczyk, M., Awad, O., Ławiński, M., Horbańczuk, J. O., Sacharczuk, M., Atanasov, A. G., Religa, P., & Mickael, M. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47050381 · Cited by 2
“While CAR T cells engineered to overexpress c-Jun have shown enhanced expansion and anti-tumor potency in mouse models, clinical trials assessing their impact on neurological symptoms are still pending [70,71].”
Fattori, S., Gorvel, L., Rouviére, M.-S., Granjeaud, S., Amara, A. B., Richaud, M., Boucherit, N., Tarpin, C., Pakradouni, J., Hedou, J. J., et al. (2025) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-24-1285 · Cited by 2
Gehrke, L., Seifert, N., Spieler, P., Verbruggen, C., Seifert, R., Toppeta, F., Krick, M., Doose, S., Einsele, H., Hudecek, M., et al. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1632823 · Cited by 2
“Cells were stained as previously described (35, 36).”
Comparative Preclinical Analysis of Anti-B7-H3 CAR-T Cells Targeting Neuroblastoma
Lutskovich, D. V., Meleshko, A., Stepanova, V. M., Dormeshkin, D., & Rubtsov, Y. P. (2025) · Biomedicines · doi:10.3390/biomedicines13092130 · Cited by 2
“This includes the co-expression of the ∆ 133p53a gene isoform [24] and the c-jun transcription factor [25], as well as the knockout of the BATF gene [26].”
Cancer gene therapy: historical perspectives, current applications, and future directions
Zeng, J., Luo, J., & Zeng, Y. (2025) · Functional & Integrative Genomics · doi:10.1007/s10142-025-01712-z · Cited by 3
“Additional limitations include the lack of truly tumor-specific Surface antigens, frequent antigen escape variants, and manufacturing challenges Like the 3–4 week production time and 15–20% failure rates (Lynn et al. 2019).”
CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells
Çobanoğlu, D. A., Franklin, S., Hu, Y., Boland, D. J., & Song, X. (2026) · Metabolites · doi:10.3390/metabo16010052 · Cited by 2
“Our results predict that MR-CAR T cells will better resist exhaustion under repetitive stimulation—an idea supported by the maintained NF-κ B activity and higher c-Jun/Fos (AP-1) levels, since sustained AP-1 has been linked to exhaustion prevention [32].”
CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency
Bucher, P., Brückner, N., Kortendieck, J., Grimm, M., Schleicher, J. T., Bartels, K., Hardy, S., Rausch, M., Wurzer, H., Thiemann, M., et al. (2026) · Nature Cancer · doi:10.1038/s43018-025-01099-7 · Cited by 2
“Consistent with these findings, gene set enrichment analysis (GSEA) comparing CD19 CAR T cells to exhaustion-prone HA CAR T cells 45 revealed transcriptional similarities of the exhaustion-like CD4⁺ T cell cluster to HA CAR T cells.”
InfluentialCD8+ T cell aging, senescence, and related disease
He, Z., Guo, F., Zhao, Q., & Lu, W. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3101-7 · Cited by 3
Granzyme B-mimetic nanozyme for nanovesicle targeted anticancer applications
Hu, X., Liu, Q., Kang, H., Zhao, M., Zhou, Z., Li, Y., Peng, W., Qi, T., Liu, R., Jiao, L., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68773-x · Cited by 2
Lee, H. J., Hwang, S. J., Jeong, E. H., Chang, M. H., Heo, B. Y., Kwon, J., Noh, Y., & Nah, J. (2026) · The Journal of Microbiology · doi:10.71150/jm.2510017 · Cited by 2
“…such as bispecific CARs, transcriptional regulatory element design, tyrosine kinase inhibitors, and oncolytic virus combinations have rapidly evolved to enhance therapeutic efficacy against solid tumors (Ghartey-Kwansah et al., 2018; Lynn et al., 2019; Mestermann et al., 2019; Miao et al., 2021).”
Strategies and mechanisms for the enhancement of chimeric antigen receptor T-cell functions
Han, S. Z., Yue, J., Zheng, H., Huang, Y., Kong, D., Wei, G., Hu, Y., & Huang, H. (2026) · Science China Life Sciences · doi:10.1007/s11427-025-3061-8 · Cited by 2
Navarro, V., Iacoboni, G., Camarillas, S., Carpio, C. D. C., Sánchez-Salinas, M. A., Feijóo, S., Bosch, F., Villacampa, G. J., & Barba, P. (2026) · Bone Marrow Transplantation · doi:10.1038/s41409-026-02803-6 · Cited by 2
Dasatinib boosts γδ T cell expansion and memory phenotypes with enhanced antitumor immunity
Lin, J.-R., Song, Y., Chou, Y., Chen, Y.-J., Hsiao, C., Li, J., Ho, Y., Liao, W.-C., Yen, H., & Liu, C.-H. (2026) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-026-04335-w · Cited by 2
“However, prolonged culture may lead to cellular exhaustion, impaired memory phenotypes, and reduced antitumor functions [17–19].”
Lan, F., Song, J., Chen, X., & (9093), Y. Z. (2026) · Molecular Immunology · doi:10.1016/j.molimm.2026.02.011 · Cited by 3
Ma, X., Zhang, Y., Wang, Y., Han, F., Lu, Y., Tong, C., Guo, Y., Wei, J., Zhu, Q., Dong, L., et al. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02597-5 · Cited by 2
“40 While the overexpression of BATF, another AP-1 family member, has been shown to enhance CAR T-cell persistence and reduce exhaustion, 41 the genetic deletion of BATF was reported to confer similar bene fi ts by suppressing exhaustion markers in a distinct experimental model.”
Application of CAR-T therapy in solid tumors: current opportunities and challenges
Wang, A., Ye, X., Zhao, Y., Huang, D., & Zhang, C. (2026) · Cancer Gene Therapy · doi:10.1038/s41417-026-01033-8 · Cited by 2
van den Broecke, L., der Vreken, A. V., Watté, F., Meeus, F., Veirman, K. D., Breckpot, K., Bruyne, E. D., & Menu, E. (2026) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-026-02923-x · Cited by 3
Picanço-Castro, V., Bonamino, M., Ramos, R., Guerino-Cunha, R., Oliveira, T. G., & Rego, E. (2021) · Hematology, Transfusion and Cell Therapy · doi:10.1016/j.htct.2021.09.008 · Cited by 2
Mechanisms of Resistance and Relapse After CAR-T Cell Therapy
Selli, M. E., Dalal, P., Neelapu, S. S., & Singh, N. (2022) · Cancer drug discovery and develogment/Cancer drug discovery and development · doi:10.1007/978-3-030-87849-8_12 · Cited by 2
PRECLINICAL MOUSE MODELS IN ADOPTIVE CELL THERAPIES OF CANCER
Rajčević, U., & Smole, A. (2022) · Slovenian Veterinary Research · doi:10.26873/svr-1513-2022 · Cited by 2
CAR T-Cell Therapy in Solid Tumors: Current Review and Future Perspectives
Zheng, J. (2023) · Highlights in Science Engineering and Technology · doi:10.54097/hset.v54i.9841 · Cited by 3
Genome Editing for Engineering the Next Generation of Advanced Immune Cell Therapies
de Lima, S. C. G., Fantacini, D. M. C., Furtado, I. P., Rossetti, R., Silveira, R. M., Covas, D. T., & de Souza, L. E. B. (2023) · Advances in experimental medicine and biology · doi:10.1007/978-3-031-33325-5_6 · Cited by 2
The invisible hand: How epigenetics shapes CAR T cell destiny
Ali, A. M., Zhang, Y., & DiPersio, J. F. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.05.007 · Cited by 2
Wang, X., Feng, Y., Wang, F., Lin, Z., Huang, J., Li, Q., Luo, H., Liu, X., Zhai, X., Gao, Q., et al. (2024) · The Journal of Gene Medicine · doi:10.1002/jgm.3712 · Cited by 2
Nunoya, J.-I., Imuta, N., & Masuda, M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168662 · Cited by 2
PcoCas12a: A novel CRISPR enzyme from Prevotella copri enhancing TCR-T-cell tumor suppression
Guo, Q., Huang, L., Liu, Y., Qi, C., Shao, H., Peng, J., Zhang, H., Zang, Y., Luo, M., Shen, X., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.139740 · Cited by 2
Dinesh, R. K., Wang, X., Mohammad, I., Gunasekaran, P., Stiklioraitis, K., Villafuerte, J. R., Rao, A., Hernández-López, R. A., Sunwoo, J. B., & Cong, L. (2026) · Nature Communications · doi:10.1038/s41467-026-76374-x · Cited by 2
Adoptive CD8+ T cell therapy generates immunological memory to inhibit melanoma metastasis.
Fu, J., Yu, A., Tang, J., He, B., & Chen, W. (2020) · PubMed Central · Cited by 2
Orthogonal engineering of synthetic T cell states to enhance cancer immunotherapy
Conti, A. G., & Roychoudhuri, R. (2023) · Nature Immunology · doi:10.1038/s41590-023-01470-9 · Cited by 2
Li, R., Guo, H., Hou, Y., Liu, S., Wang, M., Peng, T., Zhao, X., Lu, L., Han, Y., Shao, Y., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.03.11.988253 · Cited by 2
“Second, different methods, for example, blockade of costimulatory signals in mice by others (Liu et al., 2019) and treatment of healthy donors with G-CSF in our study (Jun et al., 2004), for tolerance induction via different signaling pathways might lead to differences in gene and TF expression (Liu et al., 2019; Sosk…”
BackgroundMethodInfluentialChen, Z., Arai, E., Khan, O., Zhang, Z., Ngiow, S. F., He, Y. M., Huang, H., Manne, S., Cao, Z., Baxter, A. E., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.05.20.087379 · Cited by 2
“…therapies, there is evidence that therapeutic failures are associated with the development of exhaustion (Chen et al., 2019a; Fraietta et al., 2018) and approaches that antagonize exhaustion are actively being investigated for CAR T cells (Long et al., 2015; Lynn et al., 2019; Wei et al., 2019).”
BackgroundKan, L., Huang, Y., & Liu, Z. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106753 · Cited by 2
RetractedThe CD4 T cell epigenetic JUNB+ state is associated with proliferation and exhaustionPreprint
Mihai, I. S., Selinger, M., Boucheron, N., Forsell, M. N. E., Magalhaes, I., Trygg, J., & Henriksson, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.05.573875 · Cited by 2
“A genome-wide comparison shows that our JUNB+ are the most similar cluster to the Lynn2019 exhausted state (Figure S6a).”
BackgroundMethodInfluentialCharting a shared epigenetic pathway to CD8+ T cell dysfunction in infection and cancer
Sandor, K. D., Dániel, B., & Satpathy, A. T. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.05.020 · Cited by 1
Self-citationRafei, H., Başar, R., Rezvani, K., & Daher, M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-822620-9.00021-5 · Cited by 1
Wang, Y., Huang, J., Song, Z., Zhang, S., Guo, H., Leng, Q., Fang, N., Ji, S., & Yang, J. (2025) · Biology Direct · doi:10.1186/s13062-025-00630-1 · Cited by 1
“Overexpression of c-Jun enhanced the efficacy and persistence of CAR T cells against low-antigen tumor cells, implicating synergistic inhibitory effect of c-Jun in immunotherapy of neuroblastoma [22, 23]. c-Jun can play opposite roles in cell differentiation.”
Chromatin remodeling in lymphocytic function and fate: the multifaceted roles of SWI/SNF complex
Miao, R., Liu, Y., Shen, S., Wang, W., & Wang, S. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1575857 · Cited by 1
“…the knockdown of exhaustion markers such as BATF, IRF4, TOX, NR4A, TIGIT, PD-1, and TIM-3 can extend the persistence of CAR-T cells in the body (50, 145 – 150), while targeting the upregulation of effector genes such as C-JUN can effectively enhance the effector function of CAR-T cells (151).”
Advances in chimeric antigen receptor-T therapies to target tumor resistance in B-cell malignancies
Salem, N., & Hamieh, M. (2025) · Current Opinion in Hematology · doi:10.1097/moh.0000000000000892 · Cited by 1
Jurcău, M. C., Iovanovici, D. C., Jurcău, A., Militaru, M., Udrea, R. B., Comanescu, A. D., & Nunkoo, V. S. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26189009 · Cited by 2
“The overexpression of transcriptional regulators that oppose exhaustion (for example, c-Jun) [240] or armoring the CAR-T cell construct with supportive cytokines [241] also enhances persistence.”
Li, J., Sun, H., Li, W., Zhao, N., Guo, Z., Chen, J., & Yu, J. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104968 · Cited by 1
Xu, C., Lu, C., Wang, W., Wang, Z., Qiu, Y., Han, M. H., Yang, J., & Li, S. (2025) · Immunologic Research · doi:10.1007/s12026-025-09689-4 · Cited by 1
“It has been reported that c-Jun can participate in regulating T cell proliferation, survival, cytokine production, and differentiation [24, 39–41].”
Shi, D., Yan, X., Liu, J., Chen, H., Wang, X., Li, R., Tian, X., Lin, X., & Wang, Y. (2025) · Lung Cancer · doi:10.1016/j.lungcan.2025.108849 · Cited by 1
Introducing arginine residues into scFv in CAR-T cells shows promising antitumor effects
Maeta, S., Fukunaga, A., Egashira, Y., Akahori, Y., Wang, L., Seo, N., Atarashi, Y., Ejima, D., Fujiwara, H., & Shiku, H. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.12.006 · Cited by 1
Rational redesign of antigen binding domain improves in vivo efficacy of the CD22-CAR
DeGolier, K., Pham‐Danis, C., Burciaga, S. D., Walsh, Z. H., Brzezinski, C. R., Novak, A. J., Leach, L., Cimons, J. M., Li, W., Zhongyu, Z., et al. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.12.037 · Cited by 2
Yoshida, Y., Machiyama, H., Wakamatsu, E., Saito, K., Takeuchi, A., Nishikawa, T., Matsushima, R., Nishi, W., Nishijima, H., Kanno, Y., et al. (2026) · Communications Biology · doi:10.1038/s42003-025-09415-8 · Cited by 2
“…CARantigens 28 or, conversely, reducing the af fi nity between a CAR and its antigen 29 ; overexpressing c-Jun 30 fusing the cytoplasmic domainof CTLA-4 to the C-terminus of CARs 31 and inserting the marker sequence for protein digestion 32 .”
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
