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NR4A transcription factors limit CAR T cell function in solid tumours
Open accessAbstract
T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies 1,2. CAR T cells have been less effective against solid tumours 3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state 6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections 13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.
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“Because Nr4a2 is highly related to Nr4a1 and has been found to promote T cell exhaustion (33-35),”
From Bile acid synthesis impedes tumor-specific T cell responses during liver cancer (2025) · cites this paper as [34]
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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 [15]
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“NFAT-induced transcription factors, including NR4A and TOX, drive T cell exhaustion/dysfunction44–47.”
From Tumor-specific cholinergic CD4+ T lymphocytes guide immunosurveillance of hepatocellular carcinoma (2023) · cites this paper as [44]
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Citations
Cites
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love, M. I., Huber, W., & Anders, S. (2014) · Genome Biology · doi:10.1186/s13059-014-0550-8 · Cited by 95,106
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
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
limma powers differential expression analyses for RNA-sequencing and microarray studies
Ritchie, M. E., Phipson, B., Wu, D., Hu, Y., Law, C. W., Shi, W., & Smyth, G. K. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv007 · Cited by 40,458
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
Langmead, B., Trapnell, C., Pop, M., & Salzberg, S. L. (2009) · Genome Biology · doi:10.1186/gb-2009-10-3-r25 · Cited by 21,849
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072
Heinz, S., Benner, C., Spann, N., Bertolino, E., Lin, Y. C., Laslo, P., Cheng, J. X., Murre, C., Singh, H., & Glass, C. K. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.004 · Cited by 13,382
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1504030 · Cited by 8,157
Buenrostro, J. D., Giresi, P. G., Zaba, L. C., Chang, H. Y., & Greenleaf, W. J. (2013) · Nature Methods · doi:10.1038/nmeth.2688 · Cited by 6,422
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
Maude, S. L., Frey, N., Shaw, P. A., Aplenc, R., Barrett, D. M., Bunin, N. J., Chew, A., Gonzalez, V. E., Zheng, Z., Lacey, S. F., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1407222 · Cited by 5,413
Cited by
Sorted by citations
Items 401–500 of 872
NR4A1 counteracts JNK activation incurred by ER stress or ROS in pancreatic β‐cells for protection
Pu, Z., Liu, D., Mouguegue, H. P. P. L., Jin, C., Sadiq, E., Qin, D., Yu, T., Zong, C., Chen, J., Zhao, R., et al. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.16028 · Cited by 18
Self-citationTay, T., Bommakanti, G., Jaensch, E. S., Gorthi, A., Reddy, I. K., Hu, Y., Zhang, R., Doshi, A. S., Tan, S. L., Brucklacher-Waldert, V., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101804 · Cited by 23
The ubiquitin ligase KLHL6 drives resistance to CD8+ T cell dysfunction
Cheng, H., Su, Y., Pan, X., Xu, Y., Xie, E., Du, J., Chen, D. G., Dai, X., Gottardo, R., Greenberg, P. D., et al. (2026) · Nature · doi:10.1038/s41586-025-09926-8 · Cited by 18
Liu, C., Xu, X., Han, L., Wan, X., Zheng, L., Li, C., Liao, Z., Xiao, J., Zhong, R., Zheng, X., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2000970117 · Cited by 18
“Thus, targeting inhibitory signaling proteins to improve CAR T cell therapy has been recently implicated, such as depleting diacylglycerol kinase (3) and all three NR4A transcription factors NR4A1, NR4A2, and NR4A3 (4, 5).”
BackgroundRole of NR4A family members in myeloid cells and leukemia
Boulet, S., Le Corre, L., Odagiu, L., & Labrecque, N. (2022) · Current Research in Immunology · doi:10.1016/j.crimmu.2022.02.001 · Cited by 17
“It was recently shown that NR4A expression in tumor infiltrating lymphocytes has an impact on tumor control (Chen et al., 2019; Liu et al., 2019; Odagiu et al., 2020).”
Li, X., Chen, Q., Liu, J., Lai, S., Zhang, M., Zhen, T., Hu, H., Gao, X., Wong, A. S. T., & Zeng, J.-Z. (2022) · Cells · doi:10.3390/cells11233870 · Cited by 17
“The overexpression of Nur77 also limits CART T-cell function [9].”
BackgroundShukla, S., Kumari, S., Bal, S. K., Mónaco, D. C., Ribeiro, S. P., Sékaly, R., & Sharma, A. (2021) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0000000000000692 · Cited by 17
“However, in chronic infections [HIV, hepatitis C virus (HCV), hepatitis B virus (HBV)] and cancers, when immune cells can not eliminate the tumor or the virus, persistent antigen stimulation leads to T cell intrinsic molecular events that trigger a crippled 216 www.co-hivandaids.com functional state known as exhaustio…”
BackgroundInfluentialYu, F., Liu, L., Li, J., Huang, J., Xie, J., Menard, L. C., Shi, Y., Zhao, X., Xie, S., Zang, W., et al. (2021) · Oncology Reports · doi:10.3892/or.2021.8249 · Cited by 17
Nesterenko, P. A., McLaughlin, J., Cheng, D., Bangayan, N. J., Sojo, G. B., Seet, C. S., Yu, Q., Mao, Z., Obusan, M. B., Phillips, J. W., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021190118 · Cited by 16
“More recently, the Nur77 family of transcription factors has been implicated in T cell exhaustion, which further confirms its role in T cell receptor signaling (68).”
Zhang, L., Guo, X., Sun, X., Liao, J., Liu, Q., Ye, Y., Yang, Z., Cressey, R., He, Q., & Yuan, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1486329 · Cited by 16
“However, there are many unknown factors regarding the biological and clinical signi fi cance of these receptors; the evaluation of these factors is crucial for the rational design of immunotherapy (29, 30).”
Presetting CAR-T cells during ex vivo biomanufacturing
Wang, X., Liao, Y., Liu, D., Zheng, J., & Shi, M. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.02.031 · Cited by 19
Deciphering the role of histone modifications in memory and exhausted CD8 T cells
Huang, H., Baxter, A. E., Zhang, Z., Good, C. R., Alexander, K. A., Chen, Z., Garcia, P. A. A., Samareh, P., Collins, S. M., Glastad, K. M., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-99804-0 · Cited by 17
“Whereas NUR77 (NR4A1) was highly ranked in T EX compared to T MEM based on chromatin accessibility 63,64 , this TF had comparable rankings in T EX and T MEM when assessed using enhancer-biased H3K27ac sites (Fig.”
Atlas-guided discovery of transcription factors for T cell programming
Chung, H. K., Liu, C., Battu, A., Jambor, A. N., Pratt, B. M., Xie, F., Riesenberg, B., Casillas, E., Sun, M., Landoni, E., et al. (2026) · Nature · doi:10.1038/s41586-025-09989-7 · Cited by 21
“Previously, differential TF cooperation in different contexts was reported 25,42,43 .”
Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence
Le, P. T., Ha, N., Tran, N. K., Newman, A. G., Esselen, K. M., Dalrymple, J. L., Schmelz, E. M., Bhandoola, A., Xue, H., Singh, P. B., et al. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.738958 · Cited by 16
“Our fi ndings together with those of others (22, 47, 48) illustrate the complex mechanisms governing CD8 + T-cell effector differentiation and function within a given TME.”
The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy
Wang, Y., Bui, T., & Zhang, Y. (2022) · International Journal of Hematology · doi:10.1007/s12185-022-03466-x · Cited by 17
“TFs, such as NR4A1, NFAT2, and TOX, are found to control these phenotypes [66, 67].”
BackgroundGenetic retargeting of E3 ligases to enhance CAR T cell therapy
Lane, I. C., Kembuan, G. J., Carreiro, J., Kann, M. C., Lin, W. M., Bouffard, A. A., Kreuzer, J., Morris, R. T., Schneider, E. M., Kim, J. Y., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.10.024 · Cited by 17
Yang, Y., Wang, Y., Wang, Z., Yan, H., Gong, Y., Hu, Y., Jiang, Y., Wen, S., Xu, F., Wang, B., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01351-9 · Cited by 18
“14,15) and T-BET 15 induce transcriptional programmes required for SLEC dif-f erentiation, whereas NR4A 16 and TOX 17 promote the formation of terminally exhausted subpopulations.”
Optimizing T Cell-Based Therapy for Glioblastoma
Karachi, A., Dastmalchi, F., Nazarian, S., Huang, J., Sayour, E. J., Jin, L., Yang, C., Mitchell, D. A., & Rahman, M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.705580 · Cited by 16
“Persistent antigen exposure leads to upregulation of transcription factor TOX and alterations of nuclear factor activated T cells (NFAT), which is required for formation of exhausted T cells (37, 38).”
BackgroundServaas, N. H., Hiddingh, S., Chouri, E., Wichers, C. G. K., Affandi, A. J., Ottria, A., Bekker, C. P. J., Cossu, M., Silva‐Cardoso, S. C., van der Kroef, M., et al. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42319 · Cited by 17
The landscape of chimeric antigen receptor T cell therapy in breast cancer: Perspectives and outlook
Zhang, H., Zhu, S., Deng, W., Li, R., Zhou, H., & Xiong, H. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.887471 · Cited by 19
Strong Basal/Tonic TCR Signals Are Associated with Negative Regulation of Naive CD4+ T Cells
Zinzow-Kramer, W. M., Kolawole, E. M., Eggert, J., Evavold, B. D., Scharer, C. D., & Au‐Yeung, B. B. (2022) · ImmunoHorizons · doi:10.4049/immunohorizons.2200051 · Cited by 15
Patel, C. H., Dong, Y. W., Koleini, N., Wang, X., Dunkerly-Eyring, B. L., Wen, J., Ranek, M. J., Bartle, L. M., Henderson, D. B., Sagert, J. G., et al. (2023) · JCI Insight · doi:10.1172/jci.insight.167829 · Cited by 13
“For the B16 adoptive T cell therapy models, naive C57BL/6J WT mice received a s.c. injection of 2.5 × 10 5 B16-OVA melanoma cells (gift of Hyam Levitsky, Century Therapeutics, Seattle, Washington, USA) cultured in vitro under OVA selection media containing 400 μ g/mL G418 (Invitrogen) or 5 × 10 5 B16-OVA-CD19 (provide…”
MethodInfluentialFu, Z., Huang, Z., Xu, H., Liu, Q., Li, J., Song, K., Deng, Y., Tao, Y., Zhang, H., Wang, P., et al. (2024) · Journal of Clinical Investigation · doi:10.1172/jci178558 · Cited by 18
“In addition, targeted deletion or inhibition of genes such as TGFBRII , NR4A , and DNMT3A and BET proteins, Ragnase-1, and Roquin-1 has been shown to reduce T cell exhaustion, promote CAR-T cell persistence, and/or enhance antitumor activity (12–16).”
Prognostic Biomarkers for Melanoma Immunotherapy
Twitty, C., Huppert, L. A., & DAUD, A. I. (2020) · Current Oncology Reports · doi:10.1007/s11912-020-0886-z · Cited by 15
Myeloid 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
Mechanisms of T-cell Depletion in Tumors and Advances in Clinical Research
Su, X., Zhang, M., Zhu, H., Cai, J., Wang, Z., Xu, Y., Wang, L., Shen, C., & Cai, M. M. (2025) · Biological Procedures Online · doi:10.1186/s12575-025-00265-6 · Cited by 14
Liu, G., Tian, X., Wang, Q., Xu, S., Jiang, Y., Gao, Y., & Wu, Y. (2025) · Science Advances · doi:10.1126/sciadv.adx9221 · Cited by 16
“These findings underscore NR4A inhibition as a promising immunotherapeutic strategy ( 54 ).”
Ponzo, M., Drufuca, L., Buracchi, C., Sindoni, M. M., Nucera, S., Bugarin, C., Bason, R., Rossetti, G., Bonnal, R. J. P., Meli, C., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2025-011768 · Cited by 16
Aoki, T., Nishida, N., & Kudo, M. (2021) · Journal of Histochemistry & Cytochemistry · doi:10.1369/00221554211056853 · Cited by 15
Yousefi, H., Fong, J. T., & Alahari, S. K. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.777824 · Cited by 14
“An experiment was performed and showed that chimeric antigen receptor T- cells (CAR T-cells) that lacked NR4A promoted tumor regression and prolonged survival of cancer patients when compared to CAR T-cells that expressed NR4A (24).”
Wang, L., Lv, Q., Guo, J., Wang, J., & Pan, J. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.905450 · Cited by 14
“NR4A genes were recently suggested to be associated with T cell hyporesponsiveness, as evidenced by the fact that NR4A-depleted T cells exerted potent effector functions in the context of cancer and infection (Chen et al., 2019; Liu et al., 2019).”
BackgroundEggert, J., Zinzow-Kramer, W. M., Hu, Y., Kolawole, E. M., Tsai, Y.-L., Weiss, A., Evavold, B. D., Salaita, K. S., Scharer, C. D., & Au‐Yeung, B. B. (2024) · Science Signaling · doi:10.1126/scisignal.adh0439 · Cited by 14
“Moreover, Nr4a1 − / − Nr4a2 − / − Nr4a3 − / − chimeric antigen receptor (CAR) T cells show enhanced antitumor responses in a solid tumor mouse model ( 77 ).”
BackgroundBis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands
Upadhyay, S., Hailemariam, A., Mariyam, F., Hafiz, Z., Martin, G. G., Kothari, J., Farkas, E., Sivaram, G., Bell, L., Tjalkens, R. B., et al. (2024) · Biomolecules · doi:10.3390/biom14030284 · Cited by 14
Advances in breast cancer research using CRISPR/Cas9 system
Eskandari, F., Aali, M., Hadisadegh, S. N., & Azadeh, M. (2024) · Nano Select · doi:10.1002/nano.202400015 · Cited by 18
Tuning CAR T-cell therapies for efficacy and reduced toxicity
Blud, D., Reyes, P. R., Perret, R., & Weinkove, R. (2024) · Seminars in Hematology · doi:10.1053/j.seminhematol.2024.07.003 · Cited by 14
Kong, J., Wang, F., Zhao, B., Gong, M., Zhang, J., Lu, Z., Zhou, Y., Chen, L., Su, H., Wensheng, L., et al. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.565240 · Cited by 14
Sekiya, T. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.866339 · Cited by 15
“Nr4a factors induced by TCR stimulation exert various tolerogenic functions in T cells, including negative selection of self-reactive thymocytes (19–22), differentiation and maintenance of Treg cells (5–8), repression of Th-associated molecules (23), and the induction of hyporesponsive states (Figures 1A, D) (24, 25).”
BackgroundSelf-citationYu, T., Luo, C., Zhang, H., Tan, Y., & Li, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1139482 · Cited by 14
“NR4As genes play an essential role in T cell dysfunction and cause CAR T cells to enter an exhausted or dysfunctional state in solid tumors (43, 44).”
BackgroundEngineering T cells for immunotherapy of primary human hepatocellular carcinoma
Galva, L. D. C., Cai, L., Shao, Y., & He, Y. (2020) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2020.01.002 · Cited by 14
Engineering Solutions for Mitigation of Chimeric Antigen Receptor T-Cell Dysfunction
Gavriil, A., Barisa, M., Halliwell, E., & Anderson, J. (2020) · Cancers · doi:10.3390/cancers12082326 · Cited by 13
“NR4A [39,40] and the type 1 transmembrane protein SLAMF6 [41].”
BackgroundInfluentialEngineering enhanced chimeric antigen receptor-T cell therapy for solid tumors
Neeser, A., Ramasubramanian, R., Wang, C., & Ma, L. (2023) · Immuno-Oncology Technology · doi:10.1016/j.iotech.2023.100385 · Cited by 13
“Similarly, eliminating nuclear receptor TF NR4As, the downstream targets of programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin-domain containing-3 (Tim-3) signaling, increased CAR-T cell response and antitumor activities.(28) The most intriguing example of increased CAR-T efficacy by inhibiting…”
BackgroundTargeting intracellular proteins with cell type-specific functions for cancer immunotherapy
Carelock, M. E., Master, R. P., Kim, M., Jin, Z., Wang, L. A., Maharjan, C. K., Hua, N., De, U., Kolb, R. H., Xiao, Y., et al. (2023) · Life Medicine · doi:10.1093/lifemedi/lnad019 · Cited by 13
“NR4A1 and its family members have been shown to be critical in maintaining the exhausted state of CD8 + T cells; thus, targeting NR4A1 may reverse CD8 + T cell exhaustion which is a major focus of current immunotherapies [110, 111].”
Chang, C., He, F., Ao, M., Chen, J., Yu, T., Li, W., Li, B., Fang, M., & Yang, T. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1200110 · Cited by 13
“, 2021), Nur77 is nevertheless widely expressed in different tissues and known to participate in a variety of processes as a transcriptional regulator in the nucleus or interaction partner modulating the function of other proteins (Chen et al., 2019; Niu et al., 2021).”
BackgroundSelf-citationMitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy
Burgermeister, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914546 · Cited by 13
“A landmark study showed that NR4A receptors limit the function of chimeric-antigen-receptor-expressing T cells (CAR-T) in solid tumors [62].”
BackgroundChen, J., Zhao, T., Hong, W., Li, H., Ao, M., Zhong, Y., Chen, X., Qiu, Y., Wang, X., Wu, Z., et al. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.07.012 · Cited by 13
“…multiple studies have demonstrated that Nur77 has an essential contribution to the progression of various types of cancer due to its critical roles in the metabolism 11 , proliferation 12 , apoptosis 13 , and invasion 14 of tumor cells, as well as tumor immunity 15 and tumor angiogenesis 16-18 .”
Self-citationLeucine zipper-based immunomagnetic purification of CAR T cells displaying multiple receptors
James, S. E., Chen, S., Ng, B. D., Fischman, J. S., Jahn, L., Boardman, A. P., Rajagopalan, A., Elias, H. K., Massa, A., Manuele, D., et al. (2024) · Nature Biomedical Engineering · doi:10.1038/s41551-024-01287-3 · Cited by 16
“Failure of CAR T cell therapy can result from poor T cell persistence and also the loss of T cell function associated with upregulation of inhibitory immune-checkpoint molecules and development of T cell exhaustion 3,7,17,18 .”
InfluentialNielsen, H. V., Yang, L., Mueller, J. L., Ritter, A. J., Hiwa, R., Proekt, I., Rackaityte, E., Aylard, D. A., Gupta, M., Scharer, C. D., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55839-5 · Cited by 12
“Notably, the Nr4a family contributes to the anergy/exhaustion transcriptome and epigenome of peripheral T cells 21,70,85 , and here we show that they may contribute to a related transcriptional program of non-deletional tolerance in the thymus as well.”
Zong, S., Mi, T., Flores, L. G., Alpert, A., Olivares, S., Patel, K. K., Maiti, S. N., McNamara, G. T., Cooper, L. J. N., & Torikai, H. (2020) · PLoS ONE · doi:10.1371/journal.pone.0228112 · Cited by 14
Cell surface‐nanoengineering for cancer targeting immunoregulation and precise immunotherapy
Wang, Y., Huang, G., Hou, Q., Pan, H., & Cai, L. (2022) · Wiley Interdisciplinary Reviews Nanomedicine and Nanobiotechnology · doi:10.1002/wnan.1875 · Cited by 13
Pan, B., Wang, Z., Yao, Y., Ke, X., Shen, S., Chen, W., Zhang, X., Qiu, J., Wu, X., & Tang, N. (2023) · Cellular Oncology · doi:10.1007/s13402-023-00830-9 · Cited by 13
Beyond CAR T cells: Engineered Vγ9Vδ2 T cells to fight solid tumors
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
“The protein they encode constitutes AP-1, which plays an important role in maintaining T cell activation and resistance to exhaustion ( 16 , 31 ).”
InfluentialBarriers and Strategies to Enhance CAR ‐T Cell Infiltration in Solid Tumours: A Systematic Review
Zhang, Y., Sun, H., Zhao, L., Zhao, N., 陈政良, He, L., Guo, Z., & Yu, J. (2026) · Immunology · doi:10.1111/imm.70094 · Cited by 17
“…this circuit, genetic interventions using CRISPR-Cas9 or shRNA to knock out key regulators like TOX or NR4A1 in CAR-T cells before infusion can prevent or delay exhaustion onset, endowing them with enhanced stem-like memory properties, superior persistence and deeper tumour infiltration [137, 138].”
CAR-T cells in solid tumors: engineering, biomarkers, translational pathways and the road ahead
Shaer, N. S. H. A., Masoud, I., Tleyjeh, A., Al-Attas, A. A., Al-Attas, M. A., Khan, M. I., & Yaqinuddin, A. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1796675 · Cited by 15
Hao, Y., Miraghazadeh, B., Chand, R., Davies, A. R., Cardinez, C., Kwong, K., Downes, M. B., Sweet, R. A., Cañete, P. F., D'Orsogna, L. J. A., et al. (2023) · Cellular and Molecular Immunology · doi:10.1038/s41423-023-01027-8 · Cited by 12
“Transient expression of NR4A orphan nuclear receptors has been reported in T cells after TCR ligation [43, 44], which could act cell intrinsically to inhibit effector T-cell development and induce hyporesponsiveness [45, 46].”
BackgroundSun, L., Ma, Z., Zhao, X., Tan, X., Tu, Y., Wang, J., Chen, L., Chen, Z., Chen, G., & Lan, P. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2023-008367 · Cited by 13
Chimeric antigen receptor T cells in the treatment of osteosarcoma (Review)
Yu, T., Jiang, W., Wang, Y., Zhou, Y. Y., Jiao, J., & Wu, M. (2024) · International Journal of Oncology · doi:10.3892/ijo.2024.5628 · Cited by 12
“T cells has shown a remarkable ability to impede tumor growth (157).”
BackgroundA Spatially Distributed Microneedle System for Bioorthogonal T Cell‐Guided Cancer Therapy
Li, L., Wang, F., Mo, S., Deng, J., Wang, X., Ai, J., Xiao, Y., Zeng, Y., Li, Q., Zhang, Y., et al. (2025) · Advanced Science · doi:10.1002/advs.202416841 · Cited by 12
Making Potent CAR T Cells Using Genetic Engineering and Synergistic Agents
Park, C. H. (2021) · Cancers · doi:10.3390/cancers13133236 · Cited by 11
Zhi, L., Su, X., Yin, M., Zhang, Z., Lü, H., Niu, Z., Guo, C., Zhu, W., & Zhang, X. (2021) · Cellular Immunology · doi:10.1016/j.cellimm.2021.104436 · Cited by 13
Chimeric Antigen Receptor T-Cell Therapy
Brookens, S. K., & Posey, A. D. (2023) · The Cancer Journal · doi:10.1097/ppo.0000000000000636 · Cited by 12
Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review
Wan, P. K.-T., Siu, M. K.-Y., Leung, T. H.-Y., Mo, X.-T., Chan, K. K. L., & Ngan, H. (2020) · Cancers · doi:10.3390/cancers12103044 · Cited by 12
“Exhausted CD8+ T cells are poorly cytotoxic and express distinctive patterns of inhibitory receptors, including PD-1, TIM-3, and LAG-3 [87,88].”
BackgroundTian, Y., Huang, B., Li, J., Tian, X., & Zeng, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.792901 · Cited by 12
Marsico, G., Sudarshan, G. C., & Siciliano, V. (2025) · Small · doi:10.1002/smll.202506429 · Cited by 11
de Juan, A., Coillard, A., Cros, A., Rigamonti, A., Alaoui, L., Sampaio, J. L., Monot, N., Balvay, A., Foussier, A., Rieux-Laucat, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66854-x · Cited by 15
“Of note, Nr4a1 , a key transcription factor in exhausted T cells dysfunction 64,65 , was overexpressed in AhR-de fi cient ‘ progenitor exhausted ’ T cells (Fig.”
Intratumoral microbiome: the double-edged sword in remodeling cancer immunotherapy
Yan, D., Yu, Y., Liang, C., Cui, Z., Shi, L., Li, G., & Ren, C. (2026) · Molecular Cancer · doi:10.1186/s12943-025-02566-6 · Cited by 11
“The manifestations include: (1) Continuous antigen stimulation leads to Tex [277–283], upregulating transcription factors such as TOX and NR4A and inhibitory receptors [284–287], and weakening T-cell function.”
Chen, Y., Xia, S., Zhang, L., Qin, X., Zhu, Z., Ma, T., Lu, S., Chen, J., Shi, X., & Ren, H. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12051830 · Cited by 12
“However, the effects of these therapies on most solid tumors fail to live up to the expectations because of the T cell exhaustion in the tumor microenvironment (TME) [10,11].”
BackgroundSelf-citationCAR-T cell technologies that interact with the tumour microenvironment in solid tumours
Taylor, C. A., Glover, M., & Maher, J. F. (2024) · Expert Review of Clinical Immunology · doi:10.1080/1744666x.2024.2380894 · Cited by 12
“…in CD19-reactive CAR T-cells resulted in reversal of the exhausted phenotype accompanied by a notable reduction in inhibitory receptor expression (PD-1, TIM-3, LAG-3), an increase in cytokine secretion and enhanced cytotoxicity with improved survival when infused into tumor-bearing mice [132,135].”
Gubser, P. M., Wijesinghe, S. K. M., Heyden, L., Gabriel, S. S., Souza, D. P. D., Hess, C., McConville, M. M., Utzschneider, D. T., & Kallies, A. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114632 · Cited by 14
Merenstein, A., Obeidat, L., Zaravinos, A., & Bonavida, B. (2024) · Cancers · doi:10.3390/cancers17010019 · Cited by 11
“These include the thymocyte selection-associated high mobility group box protein (TOX) [58], a nuclear factor of activated T cells family member [59], the nuclear receptor subfamily 4 group A (NR4A1) [23,60], and the early growth response gene 2 (EGR2).”
The mechanisms and countermeasures for CAR-T cell expansion and persistence deficiency
Bao, Y.-T., Lv, M., Huang, X., & Zhao, X. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.217771 · Cited by 11
Yukl, S. A., Khan, S., Chen, T., Trapečar, M., Wu, F. S.-Y., Xie, G., Telwatte, S., Fulop, D., Pico, A. R., Laird, G. M., et al. (2020) · Journal of Virology · doi:10.1128/jvi.01331-20 · Cited by 11
“The NR4A family of transcription repressors, NR4A1 (Nur77), NR4A2 (NURR1), and NR4A3 (NOR1), was recently shown to be enriched in dysfunctional CD8 T cells and repress effector programs by being recruited to the AP-1 binding sites and inhibiting their transcriptional function (58, 59).”
BackgroundTargeting BCMA to Treat Multiple Myeloma: Updates From the 2021 ASH Annual Meeting
Guo, R., Lu, W., Zhang, Y., Cao, X., Jin, X. K., & Zhao, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.839097 · Cited by 12
“The regulons associated with NR4A1 transcription factor that promotes Tcell exhaustion (124) also have been activated in CARHigh-T cells.”
BackgroundEffectiveness of immunological agents in non‐small cell lung cancer
Rekulapelli, A., Flausino, L. E., Iyer, G., & Balkrishnan, R. (2022) · Cancer Reports · doi:10.1002/cnr2.1739 · Cited by 11
“eliminating solid tumors, and that cancer immunotherapy using CAR-T cells would be effective if NR4A was inhibited.(91)”
BackgroundDunn, Z. S., Qu, Y., MacMullan, M. A., Chen, X., Cinay, G. E., & Wang, P. (2023) · Human Gene Therapy · doi:10.1089/hum.2022.068 · Cited by 12
“15,16 Among them, 4-1BB signaling components have been prominent candidates given the costimulatory role of 4-1BB:4-1BBL in supporting the clonal expansion, survival, cytokine release, and effector functions of immune cells.”
Vahedi, G. (2021) · Immunological Reviews · doi:10.1111/imr.12942 · Cited by 11
Hu, K., Yin, E. T. S., Hu, Y., & Huang, H. (2021) · Current Medical Science · doi:10.1007/s11596-021-2391-5 · Cited by 11
Charmoy, M., Wyss, T., Delorenzi, M., & Held, W. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109672 · Cited by 12
“Furthermore, these cells overexpressed the exhaustion associated transcription factors Nr4a2 (Chen et al., 2019) and Figure 3.”
BackgroundWang, H., Jiang, D., Liu, L., Zhang, Y., Qin, M., Qu, Y., Wang, L., Wu, S., Zhou, H., Xu, T., et al. (2022) · OncoTargets and Therapy · doi:10.2147/ott.s382540 · Cited by 11
“Once TOX and NR4A were knockout by shRNA or CRISPR Cas9, the CD19 CAR-T cells exhibited high effective on inhibiting tumor growth and prolonging survival of tumor-bearing mice.(29,30) Good et al demonstrated that downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR-T cell therapy in solid tumors.”
BackgroundFine tuning towards the next generation of engineered T cells
Nguyen, T. T., Ho, P., Staudt, S., Grégoire, C., Ziegler-Martin, K., Jassin, M., Block, A., Hudecek, M., Melenhorst, J. J., Caers, J., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01492-8 · Cited by 11
Jankelow, A. M., Almeida-Porada, G. D., Atala, A., Sawyer, S. W., & Porada, C. D. (2025) · Stem Cells Translational Medicine · doi:10.1093/stcltm/szaf055 · Cited by 11
Harnessing the potential of gene editing technology for CAR-T cell therapy of solid tumors
Khodabandehloo, E., Rayati, M., Ahmadi, E., Naghdibadi, M., Moradi, V., & Ahmadbeigi, N. (2025) · Inflammation and Regeneration · doi:10.1186/s41232-025-00398-x · Cited by 13
“Furthermore, CRISPR/Cas9 has been used to delete several additional negative regulators of CAR T cells, including DNMT3A [160], DGK [161], TGF-β receptor II [162, 163], CISH [164], Cbl-b [165], NR4A [166], ID3 and SOX4 [167], and RASA2 [168].”
Zhu, T., Teng, X., Jiao, Q., Ren, Y., Wang, Y., & Feng, M. (2026) · Clinical and Translational Medicine · doi:10.1002/ctm2.70609 · Cited by 12
“19,114 Conversely, enforcing the expression of stemness-associated factors (e.g., TCF-1) promotes a progenitor-like state, thereby enhancing persistence.”
InfluentialA guide to CAR T cell therapies: development, current status and future prospects
Rafei, H., Upadhyay, R., & Sharma, P. (2026) · Nature reviews. Immunology · doi:10.1038/s41577-026-01322-1 · Cited by 14
Prospects and challenges of CAR-T in the treatment of ovarian cancer
Chen, B., & Liu, J. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112112 · Cited by 11
Functional subsets of tumor-specific CD8+ T cells in draining lymph nodes and tumor microenvironment
Huang, Q., Xu, L., & Ye, L. (2024) · Current Opinion in Immunology · doi:10.1016/j.coi.2024.102506 · Cited by 11
Supercharging CAR-T cells through transcriptional and epigenetic armoring
Qin, D., Lei, Y., Shu, P., Zhang, Y., Loh, Y., Wang, Y., & Li, Q. (2025) · Theranostics · doi:10.7150/thno.107908 · Cited by 13
“Chen and colleagues also explored the function of NR4A TFs in CAR-T cells [50].”
Hdac1 as an early determinant of intermediate-exhausted CD8 + T cell fate in chronic viral infection
Hu, W., Hu, S. S., Zhu, S., Peng, W., Badovinac, V. P., Zang, C., Zhao, X., & Xue, H. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2502256122 · Cited by 12
Comparative Profiling and Chemogenomics Application of Chemical Tools for NR4A Nuclear Receptors
Willems, S., Morozov, V., Marschner, J. A., & Merk, D. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00459 · Cited by 10
Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection
Kanev, K., & Zehn, D. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.10.003 · Cited by 10
Precision Tools in Immuno-Oncology: Synthetic Gene Circuits for Cancer Immunotherapy
Bonfá, G., Blazquez-Roman, J. L., Tarnai, R., & Siciliano, V. (2020) · Vaccines · doi:10.3390/vaccines8040732 · Cited by 12
Herdt, O., Reich, S., Medenbach, J., Timmermann, B., Olofsson, D., Preußner, M., & Heyd, F. (2020) · RNA Biology · doi:10.1080/15476286.2020.1732701 · Cited by 10
“(D) Fold change of Nr4a1 mRNA expression in EL4 cell clones measured by RT-qPCR and normalized to HPRT (mean ± SD).”
BackgroundInfluentialDonkor, M., & Jones, H. P. (2021) · Frontiers in Nanotechnology · doi:10.3389/fnano.2021.635194 · Cited by 10
“It has been very successful in treating hematological malignancies but has been disappointing thus far in solid tumors due to lack of antigenic targets (Chen et al., 2019).”
BackgroundCao, H. L., Kim, D. H., Howard, A., Moz, H., Wasnik, S., Baylink, D. J., Chen, C.-S., Reeves, M. E., Mirshahidi, S., Xiao, J., et al. (2021) · Neoplasia · doi:10.1016/j.neo.2021.11.003 · Cited by 11
Lamarche, C., Novakovsky, G., Qi, C. N., Weber, E. W., Mackall, C. L., & Levings, M. K. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.27.175158 · Cited by 10
“…to modulate signaling pathway activity for example by use of kinase inhibitors (Dufva et al., 2020; Mestermann et al., 2019; Weber et al., 2019; Weber et al., 2020b), or modulation of transcription factor expression (Chen et al., 2019; Lynn et al., 2019), could be strategies to limit this risk.”
BackgroundInfluentialChoi, J. E., & Kim, T. J. (2023) · Current Issues in Molecular Biology · doi:10.3390/cimb45040220 · Cited by 12
“Laboratory analyses have shown that the Nr4a family of nuclear receptor transcription factors initiates the nuclear factor of activated T cells (NFAT), which can induce CAR-T cell hyporesponsive states [66].”
BackgroundEvolving strategies to overcome barriers in CAR-T cell therapy for acute myeloid leukemia
Colonne, C. K., Kimble, E. L., & Turtle, C. J. (2024) · Expert Review of Hematology · doi:10.1080/17474086.2024.2420614 · Cited by 10
Application of adoptive cell therapy in malignant melanoma
Hu, Q., Xuan, J., Wang, L., Shen, K., Gao, Z., Zhou, Y., Wei, C., & Gu, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06093-2 · Cited by 9
Wang, H., Qiu, B., Li, X., Ying, Y., Wang, Y., Chen, H., Zeng, F., Shi, J., Huang, J., Wu, Z., et al. (2025) · Translational Oncology · doi:10.1016/j.tranon.2025.102347 · Cited by 13
“NR4A1, a transcriptional effector of the CD8 + T -cell depletion program [47], is associated with CD8 + T -cell dysfunction [48], inhibits cytokine production in CD8 + T -cells [49], and has been found to be up-regulated in CD8 + T -cell expression.”
Chen, W., Chang, Y.-L., Lin, S., Protzer, U., Isogawa, M., Yang, H., & Huang, L. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009827 · Cited by 10
Metadata
- Authors
- Chen, J., López-Moyado, I. F., Seo, H., Lio, C.-W. J., Hempleman, L. J., Sekiya, T., Yoshimura, A., Scott-Browne, J. P., & Rao, A.
- Affiliations
- La Jolla Institute for Immunology (US)
- National Center for Global Health and Medicine (JP)
- Keio University (JP)
- Corresponding author
- Chen, Joyce
- Scott-Browne, James P.
- Rao, Anjana
- ORCID
- Venue
- Nature
- Published
- 2019-02-27
- Volume
- 567
- Issue
- 7749
- Pages
- 530-534
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6546093
- OpenAlex
- W2917547201
- Cited by
- 874
- References
- 47
- Citations by year
- 2026: 136 · 2025: 127 · 2024: 122 · 2023: 134 · 2022: 101 · 2021: 121 · 2020: 93 · 2019: 40
- FWCI
- 37.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Institutes of Health (1s10od016262-01)
- Japan Society for the Promotion of Science (18H02673, 19H04822, 16KT0114, 17H06175, 16K15292)
- National Institute of General Medical Sciences (T32GM007752)
- National Institute of Allergy and Infectious Diseases (R01AI109842, R01AI048213, R56AI109842, R01AI040127)
- National Institute of Dental and Craniofacial Research (U01DE028227)
- National Center for Research Resources (S10RR027366)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Receptors and Signaling
- Keywords
- Nur77, Nurr1, NOR-1, chimeric antigen receptor T cells, CD19, T cell exhaustion, solid tumors, chromatin accessibility, NFAT, PD-1, TIM-3, tumor-infiltrating lymphocytes, effector T cells, cancer immunotherapy, transcriptional reprogramming
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Receptors, Steroid, Receptors, Thyroid Hormone, Transcription Factors, Survival Rate, Lymphocytes, Tumor-Infiltrating, NF-kappa B, CD8-Positive T-Lymphocytes, Transcription Factor AP-1, Antigens, CD19, Adoptive Transfer, Gene Expression Profiling, Cell Line, Tumor, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2
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