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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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InfluentialTargeting Lineage-Specific Functions of NR4A1 for Cancer Immunotherapy
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“Nr4a can promote CAR-T cell exhaustion and loss of function [122].”
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“Another team showed that during T-cell exhaustion, epigenetic remodeling promoted the recruitment of NR4A family members to the promoter/enhancer regions of the PDCD1 and TOX genes [49].”
BackgroundQian, Y., Jin, N., Rao, S., Wang, Y., Li, X., Pan, W., Huang, P., Wang, S., Li, P.-F., Lv, Y., et al. (2025) · npj Breast Cancer · doi:10.1038/s41523-025-00785-0 · Cited by 6
“In contrast, the absence of NR4As on chimeric antigen receptor T cells (CAR T cells) promoted tumor regression and prolonged patient survival in solid tumors 19 .”
Liu, Y., Hao, Y., Zhang, J., Zhang, M., Chen, J., Xia, Z., Chen, M., Lv, X., Ma, X., Zhou, Y., et al. (2025) · National Science Review · doi:10.1093/nsr/nwaf306 · Cited by 6
Self-citationHao, Q., Zhou, T. Y., Yan, H., Ren, Z., Mao, W., Huang, L., Chen, Y.-Y., Wang, Y., Xiao, M., He, Y., et al. (2026) · Molecular Cancer · doi:10.1186/s12943-025-02548-8 · Cited by 9
“In contrast, NR4A1, a transcription factor implicated in negative regulation of T cell activation and exhaustion [70, 71], was significantly elevated in Traj2 (Fig.”
Jordana-Urriza, L., Serrano, G., Camara-Peña, S., Calleja-Cervantes, M. E., Martín‐Úriz, P. S., Zabaleta, A., Oliver‐Caldés, A., Español‐Rego, M., Alignani, D., Lozano, T., et al. (2026) · Blood Neoplasia · doi:10.1016/j.bneo.2026.100203 · Cited by 6
“Patient 3 exhibited lower activity of exhaustion-associated regulons ( CREM, NR4A2 , and PRDM1 ) and higher activity of memory-and infiltration-related factors ( RUNX3, TCF7 , and ID2 46-48 ; Figure 4E), consistent with sustained CAR T-cell persistence and a less differentiated phenotype.”
InfluentialKrüppel-like factors 2 and 3 regulate T cell exhaustion by directing T cell residency and migration
Shen, J., Brown, R. J., Zhang, Y., Gai, K., Brown, A. K., Bauer, A. M., Zhu, A. R., Lin, S., Niu, H., Kharel, A., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.02.021 · Cited by 7
Shumnalieva, R., Velikova, T. V., & Monov, S. V. (2024) · International Journal of Rheumatic Diseases · doi:10.1111/1756-185x.15182 · Cited by 6
“38 Additional limiting factors for CAR T-cell efficacy in both hematological and solid malignancies are severe adverse events (including life-threatening toxicity), antigen escape, restricting trafficking, modest anti-tumor activity, etc. 39 Approaches with genetic modifications in CAR structure…”
BackgroundShi, H., Chen, L., Wang, T., Zhang, W., Liu, J., Huang, Y., Li, J., Qi, H., Wu, Z., Wang, Y., et al. (2024) · Cell Death Discovery · doi:10.1038/s41420-024-02019-x · Cited by 6
“Examination of lymphocytes that had in fi ltrated the tumor revealed that Nur77 was overexpressed in fatigued T cells, and that Nur77 was associated with increased expression of Tim3 and PD-L1, decreased expression of cytokines, and decreased levels of cell death [30].”
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 .”
BackgroundTMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction
Vredevoogd, D. W., Apriamashvili, G., Levy, P. L., Sinha, S., Huinen, Z. R., Visser, N. L., de Bruijn, B., Boshuizen, J., Veen, S. E. V. H.-V., Ligtenberg, M. A., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010145 · Cited by 6
Correlative studies reveal factors contributing to successful CAR-T cell therapies in cancer
Yao, C., & Davis, K. L. (2024) · Cancer and Metastasis Reviews · doi:10.1007/s10555-024-10232-4 · Cited by 6
“Knockouts of NR4A or TOX transcription factors in CAR-T cells led to more effective suppression of tumor growth and prolonged survival in tumor-bearing mice [26, 27].”
Zhao, X., Bao, L., Qian, Y., Zhou, S., Chen, C., Ma, Z., Xu, J., Li, M., Niu, W., Wang, W., et al. (2025) · Oncogene · doi:10.1038/s41388-025-03475-0 · Cited by 6
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
“…has shown that NFAT orchestrates a program of T cell exhaustion in the absence of AP-1-binding partners (Martinez et al, 2015) through positive regulation of the TOX/NR4A T cell exhaustion axis (Chen et al, 2019; Seo et al, 2019), leading to displacement of AP-1 binding by NR4A (Liu et al, 2019).”
The Cancer Moonshot Immuno-Oncology Translational Network at 5: accelerating cancer immunotherapies
Annapragada, A., Sikora, A. G., Marathe, H. G., Liu, S., Demetriou, M., Fong, L. H., Gao, J., Kufe, D. W., Morris, Z. S., Vilar, E., et al. (2023) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djad151 · Cited by 6
“Chen et al. (9) and Seo et al. (10) showed that NR4A inhibition and BATF overexpression, respectively, may be promising strategies for overcoming T-cell exhaustion in the tumor microenvironment and improving CAR-T therapy efficacy.”
MethodPopulation dynamics and gene regulation of T cells in response to chronic antigen stimulation
Hsiung, S., & Egawa, T. (2022) · International Immunology · doi:10.1093/intimm/dxac050 · Cited by 6
Exhaustion of T cells after renal transplantation
Wang, X., Zhang, J., Zhong, P., & Wei, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1418238 · Cited by 6
Hogan, P. G., Reveles, B. V., & Arteaga-Vazquez, L. J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1576468 · Cited by 6
Пузанов, Г. А., Astier, C., Papakonstantinou, D., Londoño, M. Q., Blériot, C., Yurchenko, A. A., Bani, M. A., Jules-Clément, G., André, F., Marabelle, A., et al. (2025) · Cancer Letters · doi:10.1016/j.canlet.2025.218127 · Cited by 6
Altshuler-Keylin, S., Caduff, N., Ishizuka, I. E., Reja, R., Nutsch, K., Gao, C., Wang, J., Kaufmann, U., Tleugabulova, M. C., Dixon, E. L., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02333-1 · Cited by 5
“Loss of AP-1 expression and reduced accessibility to chromatin regions bound by AP-1 are both associated with T cell exhaustion 44–46 .”
Makni‐Maalej, K., Alotaibi, S., Fernandes, Q., Ahmed, S. O., Mestiri, S., Bougarn, S., Amir, W., Syed, F., Kharfan‐Dabaja, M. A., Merhi, M., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1762453 · Cited by 6
Opportunities and challenges of PROTAC in the treatment of protein-driven diseases
Zhou, Z., Liu, P., Li, Y., Liu, X., & Li, J. (2026) · Results in Chemistry · doi:10.1016/j.rechem.2026.103234 · Cited by 7
Wang, Z., Wang, L. E., Ji, M., 娄杰, Yuan, Y., Cui, Y., Xiang, G., & Zhou, X. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1734880 · Cited by 5
“TOX/TOX2 and NR4A1 – 3 function as central regulators that cooperate to establish and maintain an exhaustion program through chromatin remodeling and epigenetic stabilization (90, 91).”
Transcription factors in chimeric antigen receptor T-cell development
Dai, A., Zhang, X., Wang, X., Liu, G., Wang, Q., & Yu, F. (2024) · Human Cell · doi:10.1007/s13577-024-01040-7 · Cited by 5
“In fact, in the development of CAR-T cells, a lot of methods have been employed to directly or indirectly target TFs [9, 10].”
InfluentialPregnenolone sulfate induces transcriptional and immunoregulatory effects on T cells
Hajj, Y. E., Shahin, T., Dieng, M. M., Alshaikh, M., Khair, M., Vinu, M., & Idaghdour, Y. (2024) · Scientific Reports · doi:10.1038/s41598-024-57327-0 · Cited by 5
“Moreover, Nr4a2 -/- CD8 + CAR T cells showed reduced expression of exhaustion markers and demonstrated higher tumor regression and enhanced survival in tumor-bearing mice 32 .”
BackgroundLima, A. J. F., Hajdu, K. L., Abdo, L. D. M., Batista-Silva, L. R., Andrade, C. D. O., Correia, E. M., Aragão, E. A. A., Bonamino, M., & Lourenzoni, M. R. (2024) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2024.05.032 · Cited by 5
“Other reporters that are not directly linked to the CAR molecule, such as fluorescent molecules or membrane reporters like dNGFR might be suitable alternatives, although they might pose different challenges [28,29].”
BackgroundTranscriptional rewiring in CD8+ T cells: implications for CAR-T cell therapy against solid tumours
Srinivasan, S., Armitage, J. D., Nilsson, J. A., & Waithman, J. C. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1412731 · Cited by 5
“As such, they are involved in multiple aspects of CD8 + T cell biology, including the negative selection of autoreactive thymocytes, SLEC formation, establishing peripheral tolerance, and promoting exhaustion (73, 131 – 134).”
BackgroundMethodInfluentialThe latest trends in improving CAR-T cell therapy: from leukemia to solid malignant tumors
Валерьевич, Е. А., Demyanov, G. V., Nasrullaeva, D. A., Radkevich, E. R., Долгих, В. Т., Сидорова, Н. В., Valiev, T. T., Михайловна, Е. М., Борисовна, М. Е., Киргизов, К. И., et al. (2021) · Russian Journal of Pediatric Hematology and Oncology · doi:10.21682/2311-1267-2021-8-2-84-95 · Cited by 6
EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects
Wirges, A., Bunse, M., Joedicke, J. J., Blanc, E., Gudipati, V., Moles, M. W., Shiku, H., Beule, D., Huppa, J. B., Höpken, U. E., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.07.009 · Cited by 7
Solid tumours: Building bridges to CAR‐T success
Maher, J. F. (2023) · Clinical and Translational Discovery · doi:10.1002/ctd2.179 · Cited by 5
Involvement of NY-ESO-1 and MAGE-A4 in the pathogenesis of desmoid tumors
Hashimoto, K., Nishimura, S., Shinyashiki, Y., Ito, T., Kakinoki, R., & Akagi, M. (2023) · Medicine · doi:10.1097/md.0000000000033908 · Cited by 5
“It is also possible that the TME of naïve T cells encountering antigens in DTs can cause T cell dysfunction, such as functional memory, exhaustion, tolerance, anergy, and senescence.[28,29] The present study has several limitations.”
BackgroundT cell exhaustion: Focus on molecular pathways
Dang, Q. (2025) · Pathology - Research and Practice · doi:10.1016/j.prp.2025.156081 · Cited by 5
El receptor nuclear NOR-1 (Neuron-derived Orphan Receptor-1) en el remodelado vascular patológico
Ballester‐Servera, C., Cañes, L., Alonso, J., Puertas-Umbert, L., Taurón, M., Rodrı́guez, C., & Martínez‐González, J. (2022) · Clínica e Investigación en Arteriosclerosis · doi:10.1016/j.arteri.2022.03.002 · Cited by 5
Dissecting the heterogeneity of exhausted T cells at the molecular level
Kagoya, Y. (2022) · International Immunology · doi:10.1093/intimm/dxac016 · Cited by 5
Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer
Zhang, L., Zhang, B., Li, L., Ye, Y., Wu, Y., Yuan, Q., Xu, W., Wen, X., Guo, X., & Nian, S. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04326-1 · Cited by 6
The Roles of RUNX Proteins in Lymphocyte Function and Anti-Tumor Immunity
Seo, W., Nomura, A., & Taniuchi, I. (2022) · Cells · doi:10.3390/cells11193116 · Cited by 5
“Interestingly, one study did identify the Nr4a nuclear receptor family member Nr4a1 in suppressing Runx3 expression and restraining CD8+ T cell development [79], but it was later demonstrated that loss of Nr4a function had no significant effects on Runx3 expression levels in CD8+ TILs (Tumor-infiltrating lymphocytes)…”
BackgroundWang, W., Guo, H., Wu, S., Xian, S., Zhang, W., Zhang, R., Chen, Z., Su, K., Zhang, Y., Zhu, Y., et al. (2023) · Reproductive Sciences · doi:10.1007/s43032-022-01134-3 · Cited by 5
“It also limited the function of cart cells in solid tumors [44].”
BackgroundYamamoto, T., Mitsunaga, F., Wasaki, K., Kotani, A., Tajima, K., Tanji, M., & Nakamura, S. (2023) · Archives of Microbiology & Immunology · doi:10.26502/ami.936500113 · Cited by 5
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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