The DOI matches its Crossref record; 46 of the 47 references it cites were found in a registry or an index.
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.
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
“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]
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 [15]
In the citing paper
“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]
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
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 301–400 of 872
Development of CAR-T cells for long-term eradication and surveillance of HIV-1 reservoir
Liu, B., Zhang, W., & Zhang, H. (2019) · Current Opinion in Virology · doi:10.1016/j.coviro.2019.04.004 · Cited by 30
NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*
Hiwa, R., Brooks, J. F., Mueller, J. L., Nielsen, H. V., & Zikherman, J. (2022) · Immunological Reviews · doi:10.1111/imr.13072 · Cited by 33
Chen, Z., Zhu, Z., Hu, T., Yao, C., & Wu, T. (2025) · Cellular and Molecular Immunology · doi:10.1038/s41423-025-01378-4 · Cited by 37
“Other TFs critical for the development of T cell exhaustion, such as NR4A family members [73, 90 – 92], NFAT-AP-1 signaling [93 – 96], and BATF/IRF4 [97 – 100], are also associated with TCR signaling.”
Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance
Qin, Y., & Xu, G. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.1053120 · Cited by 32
Naeem, M., Hazafa, A., Bano, N., Ali, R., Farooq, M., Razak, S. I. A., Lee, T. Y., & Devaraj, S. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.121409 · Cited by 32
Nr4a nuclear receptors: markers and modulators of antigen receptor signaling
Bending, D., & Zikherman, J. (2023) · Current Opinion in Immunology · doi:10.1016/j.coi.2023.102285 · Cited by 29
The epigenetic landscape of fate decisions in T cells
Jay, A., Pondevida, C. M., & Vahedi, G. (2025) · Nature Immunology · doi:10.1038/s41590-025-02113-x · Cited by 32
“Corroborating this observation, the ectopic expression of NR4A1, NR4A2 or NR4A3 can modify the chromatin accessibility landscape of CD8 + T cells, inducing changes characteristic of T cell exhaustion 24,25 .”
Epigenetics of T cell fate decision
Pace, L., & Amigorena, S. (2020) · Current Opinion in Immunology · doi:10.1016/j.coi.2020.01.002 · Cited by 30
Engineering Cytoplasmic Signaling of CD28ζ CARs for Improved Therapeutic Functions
Meng, X., Jing, R., Qian, L., Zhou, C., & Sun, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01046 · Cited by 31
“CAR-T cells lacking three NR4A proteins showed an enhanced effector function and anti-tumor effect (57).”
Backgroundβ-glucan from Lentinus edodes inhibits breast cancer progression via the Nur77/HIF-1α axis
Zhang, X., Li, T., Liu, S., Xu, Y., Meng, M., Li, X.-M., Lin, Z., Wu, Q., Xue, Y., Pan, Y., et al. (2020) · Bioscience Reports · doi:10.1042/bsr20201006 · Cited by 30
Zhang, S., Yu, F., Che, A., Tan, B., Huang, C., Chen, Y., Liu, X., Huang, Q., Zhang, W., Ma, C., et al. (2022) · Advanced Science · doi:10.1002/advs.202104132 · Cited by 28
Gamage, A. M., Chan, W. O. Y., Zhu, F., Lim, Y. T., Long, S., Ahn, M., Tan, C. W., Foo, R., Sia, W. R., Lim, X. F., et al. (2022) · Immunity · doi:10.1016/j.immuni.2022.10.008 · Cited by 30
Yu, W., He, J., Wang, F., He, Q., Shi, Y., Tao, X., & Sun, B. (2022) · Immunology · doi:10.1111/imm.13611 · Cited by 29
“Data are representative of ≥3 independent experiments (mean SEM). sites of activator protein 1 (AP-1) instead of the AP-1 targets [26, 35, 36].”
BackgroundInfluentialKatiyar, V., Chesney, J. A., & Kloecker, G. H. (2023) · Cancers · doi:10.3390/cancers15143733 · Cited by 32
“Even after successful infiltration and engagement, the durability of CAR T response is downregulated by T cell exhaustion mediated by chronic antigen stimulation and upregulation of the NR4A transcription factor family [47].”
BackgroundCoengineering specificity, safety, and function into T cells for cancer immunotherapy
Attianese, G. M. P. G., Ash, S., & Irving, M. B. (2023) · Immunological Reviews · doi:10.1111/imr.13252 · Cited by 29
Recent advances and future perspectives of CAR-T cell therapy in head and neck cancer
Hu, C., Liu, M., Li, Y., Zhao, Y., Sharma, A., Liu, H., & Schmidt‐Wolf, I. G. H. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1213716 · Cited by 30
“T-cell exhaustion is significantly influenced by the activation of the transcription factor family NR4A, which is connected to the production of immunosuppressive molecules in solid tumors such as PD-1 and TIM3.”
BackgroundmRNA-based therapeutic strategies for cancer treatment
Taibi, T., Cheon, S., Perna, F., & Vu, L. (2024) · Molecular Therapy · doi:10.1016/j.ymthe.2024.04.035 · Cited by 31
Liu, Y., Zhang, W., Wang, C.-G., Huang, J., Jiang, J.-H., & Zeng, D. (2020) · Microvascular Research · doi:10.1016/j.mvr.2020.103988 · Cited by 28
Zander, R., Khatun, A., Kasmani, M. Y., Chen, Y., & Cui, W. (2022) · eLife · doi:10.7554/elife.80079 · Cited by 28
Hepatitis E virus: from innate sensing to adaptive immune responses
Brüggemann, Y., Klöhn, M., Wedemeyer, H. H., & Steinmann, E. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00950-z · Cited by 26
“For example, targeting transcription factors, such as TOX 155–157 or NR4A 158 , as well as molecules such as TGFβ 159 or the E3 ubiquitin-protein ligase CBL-B 160 might have the potential to promote T cell function.”
Lawton, M. L., Inge, M. M., Blum, B. C., Smith-Mahoney, E. L., Bolzan, D., Lin, W., McConney, C., Porter, J., Moore, J., Youssef, A., et al. (2024) · PLoS Biology · doi:10.1371/journal.pbio.3002943 · Cited by 25
“We like-wise observed increased binding of KAT2B to another nuclear receptor group, including family member NR4A1 reported to regulate TIM-3, and possibly other inhibitory receptors [117– 119].”
Ye, Q., Lai, X., Liu, Y., Zhang, Z., Fu, Y.-Q., Luo, J., Liu, C., Duan, J., Ding, H., Liu, Y., et al. (2025) · Nature Immunology · doi:10.1038/s41590-025-02345-x · Cited by 31
“In tumors, NR4A2, along with NR4A1 and NR4A3, has been shown to drive exhaustion and limit effector functions in chimeric antigen receptor T cells 27,28 , whereas in tumor-associated NK cells, NR4A2 expression is linked to reduced cytotoxic activity and a dysfunctional state 43 .”
Leveraging Single-Cell Sequencing for Chimeric Antigen Receptor T Cell Therapies
Castellanos-Rueda, R., Roberto, R. B. D., Schlatter, F. S., & Reddy, S. T. (2021) · Trends in biotechnology · doi:10.1016/j.tibtech.2021.03.005 · Cited by 24
Ando, M., Kondo, T., Tomisato, W., Ito, M., Shichino, S., Srirat, T., Mise‐Omata, S., Nakagawara, K., & Yoshimura, A. (2021) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0034 · Cited by 29
Self-citationEmpowering the Potential of CAR-T Cell Immunotherapies by Epigenetic Reprogramming
Alvanou, M., Lysandrou, M., Christofi, P., Psatha, N., Spyridonidis, A., Παπαδοπούλου, Α., & Yannaki, E. (2023) · Cancers · doi:10.3390/cancers15071935 · Cited by 28
Regulatory Mechanisms and Reversal of CD8+T Cell Exhaustion: A Literature Review
Zhu, W., Li, Y., Han, M., & Jiang, J. (2023) · Biology · doi:10.3390/biology12040541 · Cited by 28
Continuous Expression of Interferon Regulatory Factor 4 Sustains CD8 + T Cell Immunity against Tumor
Yu, A., Fu, J., Yin, Z. Q., Yan, H. M., Xiao, X., Zou, D., Zhang, X., Zu, X., Li, X. C., & Chen, W. (2023) · Research · doi:10.34133/research.0271 · Cited by 28
“While eliminating NR4As has shown promise in improving T cell antitumor immunity in murine models [22], caution should be exercised when considering the manipulation of TOX.”
BackgroundMethodYu, X., Yu, J., Dai, H., Deng, C., Sun, X., Long, S., Jiang, Z., Jin, H., Guan, Z., & Yang, Z. (2022) · Theranostics · doi:10.7150/thno.71010 · Cited by 26
“TOX and NR4A were recently reported to be key transcription factors imposing CD8+ T cell exhaustion [54,55].”
BackgroundKnocking Out CD70 Rescues CD70-Specific NanoCAR T Cells from Antigen-Induced Exhaustion
Munter, S. D., Buhl, J. L., Cock, L. D., Parys, A. V., Daneels, W., Pascal, E., Deseins, L., Ingels, J., Goetgeluk, G., Jansen, H., et al. (2024) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-23-0677 · Cited by 28
Stem-like CD8+ T cells in cancer
Steiner, C., Denlinger, N., Huang, X., & Yang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1426418 · Cited by 28
CAR T Cell Immunotherapy Beyond Haematological Malignancy
Hupperetz, C., Lah, S., Kim, H., & Kim, C. H. (2022) · Immune Network · doi:10.4110/in.2022.22.e6 · Cited by 26
“(61) identified nuclear receptor 4A (NR4A) as a possible transcriptional effector of T cell exhaustion.”
BackgroundSynthetic dual co-stimulation increases the potency of HIT and TCR-targeted cell therapies
Dobrin, A., Lindenbergh, P. L., Shi, Y., Perica, K., Xie, H., Jain, N., Chow, A., Wolchok, J. D., Merghoub, T., Sadelain, M., et al. (2024) · Nature Cancer · doi:10.1038/s43018-024-00744-x · Cited by 23
“We found increased 19-HIT 80BB T cell accumulation in the bone marrow of leukemic mice at day 9, accompanied by less expression of inhibitory markers and transcription factors associated with T cell dysfunction 38,39,54 (Fig.”
Kennedy, P. H., Sheikh, A. A. D., Balakar, M., Jones, A. C., Olive, M. E., Hegde, M., Matias, M. I., Pirete, N., Burt, R. A., Levy, J. M., et al. (2024) · Nature Methods · doi:10.1038/s41592-024-02256-z · Cited by 30
“GZMB is the main effector molecule of the cytotoxic program and NR4As have been shown to be drivers of T cell exhaustion 59 .”
Xiang, S., Li, S., & Xu, J. (2025) · Clinical and Translational Medicine · doi:10.1002/ctm2.70345 · Cited by 28
“…the immunosuppressive roles of EATFs such as Osr2 and NR4A in solid tumours, while highlighting the therapeutic potential of targeting these TFs. 54,55 Notably, Nikhil S. Joshi’s group at Yale University employed single-cell RNA sequencing coupled with CRISPR screening to demonstrate that the…”
Clinical and molecular dissection of CAR T cell resistance in pancreatic cancer
Aznar, M. A., Good, C. R., Barber-Rotenberg, J. S., Agarwal, S., Wilson, W. V., Watts, A., Zhang, Z., Gonzales, D. M., Donahue, G., Hwang, W.-T., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102301 · Cited by 30
Regulatory T Cells: Pathophysiological Roles and Clinical Applications
Sakai, R., Komai, K., Iizuka-Koga, M., Yoshimura, A., & Ito, M. (2019) · The Keio Journal of Medicine · doi:10.2302/kjm.2019-0003-oa · Cited by 25
Self-citationBrooks, J. F., Tan, C., Mueller, J. L., Hibiya, K., Hiwa, R., Vykunta, V. S., & Zikherman, J. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109645 · Cited by 25
Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy
Chung, H., Jung, H., & Noh, J. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212126 · Cited by 28
“Similar to the approach to delete NR4A to downregulate the T cell exhaustion-related NFAT signaling [120], overexpression of AP-1 factor c-Jun can activate CAR-T cells by promoting exhaustion resistance [126].”
BackgroundMethodQuezada, L. K., Jin, W., Liu, Y. C., Kim, E. S., He, Z., Indralingam, C. S., Tysl, T., Labarta-Bajo, L., Wehrens, E. J., Jo, Y., et al. (2023) · PLoS Biology · doi:10.1371/journal.pbio.3001983 · Cited by 24
MicroRNA regulation of CD8+ T cell responses
Gagnon, J. D., & Ansel, K. M. (2019) · Non-coding RNA Investigation · doi:10.21037/ncri.2019.07.02 · Cited by 25
“A growing number of transcription factors have been implicated in T cell exhaustion including T-BET, EOMES, Spry2, BLIMP-1, VHL, FOXO1, IRF, BATF, and NFATC1 (96,101) and more recently, the NR4A family members, NR4A1, NR4A2, and NR4A3 (102).”
BackgroundThe CUL5 E3 ligase complex negatively regulates central signaling pathways in CD8+ T cells
Liao, X., Li, W., Zhou, H., Rajendran, B. K., Li, A., Ren, J., Luan, Y., Calderwood, D., Turk, B. E., Tang, W., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-44885-0 · Cited by 27
“Beyondtheenhancedeffectorfunctions,elevatedJUN 86 and BATF 87 and decreased NR4A2 protein contents may explain increased exhaustion resistance 88,89 .”
BackgroundPhenotypic and spatial heterogeneity of CD8+ tumour infiltrating lymphocytes
Sun, Y., Yinwang, E., Wang, S., Wang, Z., Wang, F., Xue, Y., Zhang, W., Zhao, S., Mou, H., Chen, S., et al. (2024) · Molecular Cancer · doi:10.1186/s12943-024-02104-w · Cited by 29
“…to monomeric binding motifs unaccompanied by an adjacent AP-1 site, inducing transcription of exhaustion-related genes encoding inhibitory molecules (e.g., Pdcd1 [encoding PD-1], Lag3 , Havcr2 [TIM3], Tigit , Ctla4 ) and repressive TFs (e.g., Tox , Egr1 , Egr2 , and Nr4a ) [86–88 , 93– 97].”
BackgroundZhu, Z., Luo, Y., Lou, G., Yihunie, K. D., Wizzard, S., DeVilbiss, A., Muh, S., Ma, C., Shinde, S. S., Hoar, J., et al. (2024) · Science Immunology · doi:10.1126/sciimmunol.adk2954 · Cited by 25
Sekiya, T., Kagawa, S., Masaki, K., Fukunaga, K., Yoshimura, A., & Τακακι, S. (2021) · iScience · doi:10.1016/j.isci.2021.102166 · Cited by 25
Self-citationGene Regulatory Circuits in Innate and Adaptive Immune Cells
Saini, A., Ghoneim, H. E., Lio, C. J., Collins, P. L., & Oltz, E. M. (2022) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101320-025949 · Cited by 24
Self-citationZhao, L., Wang, H., Xu, K., Liu, X., & He, Y. (2022) · Chinese Medical Journal · doi:10.1097/cm9.0000000000001981 · Cited by 24
“At the transcriptional level, multiple transcription regulators have been found to potentiate the expression of LAG-3, such as thymocyte selection-associated high mobility group box protein (TOX),([30,31]) a nuclear factor of activated T-cells family member,([32]) nuclear receptor subfamily 4, group A,([33]) and early…”
BackgroundSasaya, T., Kubo, T., Murata, K., Mizue, Y., Sasaki, K., Yanagawa, J., Imagawa, M., Kato, H., Tsukahara, T., Kanaseki, T., et al. (2022) · Cancer Medicine · doi:10.1002/cam4.5310 · Cited by 24
The role of transforming growth factor-β (TGF-β) in the formation of exhausted CD8 + T cells
Ma, R., Sun, J., & Wang, Y. (2024) · Clinical and Experimental Medicine · doi:10.1007/s10238-024-01394-0 · Cited by 27
“…TCF1, promoted the expression of thymocyte selection-associated high mobility group box factor (TOX) [27, 28] and nuclear receptor 4A (NR4A) [29], and led to upregulation of multiple inhibitory immune checkpoint proteins, including PD-1, T-cell immunoglobulin and mucin domain-containing…”
BackgroundImmune regulation by the SUMO family
Tharuka, M. D. N., Courelli, A. S., & Chen, Y. (2025) · Nature reviews. Immunology · doi:10.1038/s41577-025-01155-4 · Cited by 32
Speed and Location Both Matter: Antigen Stimulus Dynamics Controls CAR-T Cell Response
Liu, C., Qi, T., Milner, J. J., Lu, Y., & Cao, Y. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.748768 · Cited by 25
Genome Editing in Engineered T Cells for Cancer Immunotherapy
Bonini, C., Chapuis, A. G., Hudecek, M., Guedan, S., Magnani, C. F., & Qasim, W. (2023) · Human Gene Therapy · doi:10.1089/hum.2023.128 · Cited by 29
“126 Typically, these knockout strategies have been used to identify candidate genes, based on their previously described roles in inhibiting T cell activation or function.”
An Oral PROTAC Targeting HPK1 Degradation Potentiates Anti‐Solid Tumor Immunity
Yao, Y., Wu, M., Wang, Y., Liao, Z., Yang, Y., Liu, Y., Shi, J., Wu, W., Wei, X., Xu, J., et al. (2024) · Advanced Materials · doi:10.1002/adma.202411454 · Cited by 24
Engineering strategies of sequential drug delivery systems for combination tumor immunotherapy
Xu, Z., Liu, S., Li, Y., Wu, Y., Tu, J., Chen, Q., & Sun, C. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.05.039 · Cited by 26
“However, to present, it is still a tough mission to efficiently apply CAR-T cells in the treatment of solid tumors, where the immunosuppressive TME always leads to T cell rejection and depletion 226 .”
Loss of the orphan nuclear receptor NR2F6 enhances CD8+ T-cell memory via IFN-γ
Jakic, B., Olson, W. J., Siegmund, K., Klepsch, V., Kimpel, J., Labi, V., Zehn, D., Baier, G., & Hermann‐Kleiter, N. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03470-9 · Cited by 22
Synthetic receptors for logic gated T cell recognition and function
Simon, S., Bugos, G., Salter, A. I., & Riddell, S. R. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.09.003 · Cited by 23
Transcriptional determinants of cancer immunotherapy response and resistance
Gupta, R., Mehta, A., & Wajapeyee, N. (2022) · Trends in cancer · doi:10.1016/j.trecan.2022.01.008 · Cited by 23
Birtel, M., Voss, R.-H., Reinhard, K., Rengstl, B., Ouchan, Y., Michel, K., Hayduk, N., Tillmann, B., Becker, R., Suchan, M., et al. (2022) · Cancer Research Communications · doi:10.1158/2767-9764.crc-21-0154 · Cited by 22
“The latter state has previously been characterized by upregulation of factors like TOX/TOX2 or members of the NR4A family (70, 71).”
BackgroundSUSD2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling
Zhao, B. L., Gong, W., Ma, A., Chen, J., Velegraki, M., Dong, H., Liu, Z., Wang, L., Okimoto, T., Jones, D. M., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01326-8 · Cited by 23
Self-citationTang, L., Huang, Z., Mei, H., & Hu, Y. (2023) · Military Medical Research · doi:10.1186/s40779-023-00486-4 · Cited by 24
Qin, J., Niu, B., Chen, X., Hu, C., Sheng, L., Li, H., Liu, W., Li, J., Teng, Z., Yang, Y., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01336 · Cited by 23
Petri, K., D’Ippolito, E., Künkele, A., Koehl, U., Busch, D. H., Einsele, H., & Hudecek, M. (2025) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-025-01072-4 · Cited by 28
CAR T cell persistence in cancer
Mueller, K. P., Grenier, J. M., & Weber, E. W. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.08.014 · Cited by 22
Advancing CAR-T Therapy for Solid Tumors: From Barriers to Clinical Progress
Smirnov, S., Zaritsky, Y., Silonov, S. A., Gavrilova, A. A., & Fonin, A. V. (2025) · Biomolecules · doi:10.3390/biom15101407 · Cited by 21
“Genetic engineering efforts now routinely extend beyond CAR insertion to include knockout (KO) of inhibitory genes—e.g., CD5 or NR4A transcription factors—using CRISPR-Cas9, further enhancing the proliferative capacity and anti-tumor potency of CAR-T cells [21,22].”
Yagel, G., Rimini, D., von Locquenghien, M., Avellino, R., Barboy, O., Chalan, P., Granot, G., Xie, K., Shlomi-Loubaton, S., Sheban, F., et al. (2026) · Cancer Cell · doi:10.1016/j.ccell.2025.11.009 · Cited by 25
Reticker-Flynn, N. E., & Engleman, E. G. (2020) · eLife · doi:10.7554/elife.53839 · Cited by 23
PKR induces TGF-β and limits oncolytic immune therapy
Hong, B., Sahu, U., Mullarkey, M. P., Hong, E., Pei, G., Yan, Y., Otani, Y., Banasavadi‐Siddegowda, Y., Fan, H., Zhao, Z., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006164 · Cited by 23
Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion
Mohankumar, K., Wright, G. A., Kumaravel, S., Shrestha, R., Zhang, L., Abdelrahim, M., Chapkin, R. S., & Safe, S. H. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-023-03530-3 · Cited by 24
CRISPR/Cas9 technology: towards a new generation of improved CAR-T cells for anticancer therapies
Ureña-Bailén, G., Lamsfus‐Calle, A., Daniel-Moreno, A., Raju, J., Schlegel, P., Seitz, C. M., Atar, D., Antony, J. S., Handgretinger, R., & Mezger, M. (2019) · Briefings in Functional Genomics · doi:10.1093/bfgp/elz039 · Cited by 23
Etxeberría, I., Olivera, I., Bolaños, E., Cirella, A., Teijeira, Á., Berraondo, P., & Melero, I. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0464-1 · Cited by 23
Advances and challenges in CAR-T cell therapy for head and neck squamous cell carcinoma
Masouleh, S. S., Nasiri, K., Ravari, A. O., Rad, M. S., Kiani, K., Sultani, A. S., Nejati, S. T., & Nabi‐Afjadi, M. (2025) · Biomarker Research · doi:10.1186/s40364-025-00783-1 · Cited by 21
“Ultimately, this approach could lead to better therapeutic outcomes by preventing premature T-cell exhaustion in the harsh TME [156].”
Gong, Y., Fei, P., Zhang, Y., Xu, Y., & Wei, J. (2025) · Advanced Science · doi:10.1002/advs.202501095 · Cited by 25
Yan, Y., Lu, J., Luo, H., Wang, Z., Xu, K., Wang, L., & Wang, Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1667464 · Cited by 26
Fang, Y., Zhang, Y., Guo, C., Chen, C., Gao, H., Zhou, X., Liu, T., & Qian, Q. (2020) · Molecular Therapy — Methods & Clinical Development · doi:10.1016/j.omtm.2020.08.008 · Cited by 21
Functional heterogeneity and adaptation of naive T cells in response to tonic TCR signals
Eggert, J., & Au‐Yeung, B. B. (2021) · Current Opinion in Immunology · doi:10.1016/j.coi.2021.09.007 · Cited by 20
Sarén, T., Ramachandran, M., Gammelgård, G., Lövgren, T., Mirabello, C., Björklund, Å. K., Wikstrom, K. I., Hashemi, J., Freyhult, E., Ahlström, H. K., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-0178 · Cited by 19
“S8A–S8C) that expressed genes associated with dysfunction NR4A1, NR4A2, and NR4A3 (38, 39), functional exhaustion markers ENTPD1 and TIGIT (31, 40) and immune checkpoint CTLA4 (Fig.”
BackgroundRyu, H., Bi, T., Pulliam, T. H., Sarkar, K., Church, C. D., Kumar, N., Mayer-Blackwell, K., Jani, S., Ramchurren, N., Hansen, U. K., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101390 · Cited by 20
Zhang, Q., Jiang, L., Wang, W., Huber, A. K., Valvo, V. M., Jungles, K. M., Holcomb, E. A., Pearson, A. N., The, S., Wang, Z., et al. (2024) · JCI Insight · doi:10.1172/jci.insight.168824 · Cited by 23
Self-citationChimeric Antigen Receptor T-Cell Therapy for Multiple Myeloma
Hosen, N. (2019) · Cancers · doi:10.3390/cancers11122024 · Cited by 23
Workel, H. H., van Rooij, N., Plat, A., Spierings, D. C. J., Fehrmann, R. S. N., Nijman, H. W., & de Bruyn, M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21113770 · Cited by 20
“increased CD8+ T cell effector functions and induced tumor regression [43].”
BackgroundKumar, A., Hill, T. M., Gordy, L. E., Suryadevara, N., Wu, L., Flyak, A. I., Bezbradica, J. S., Kaer, L. V., & Joyce, S. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2001665117 · Cited by 19
“In addition, other cytokine gene loci, such as Il21 and Tnfa, showed enrichment for Nur77 without a direct Nur77-binding motif, suggesting that Nur77 can induce the expression of negative regulators of cytokine genes and thereby control T cell responsiveness (24, 26, 71).”
BackgroundWang, H., Tang, L. Y., Kong, Y., Liu, W., Zhu, X., & You, Y. H. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119115 · Cited by 19
“NR4A-knockout CAR-Ts enhanced anti-tumor function, promoted tumor reduction in vitro [4,25].”
BackgroundXiong, Y., Taleb, M., Misawa, K., Hou, Z., Banerjee, S., Amador-Molina, A., Jones, D. R., Chintala, N. K., & Adusumilli, P. S. (2023) · Nature Cancer · doi:10.1038/s43018-023-00573-4 · Cited by 19
DeGolier, K., Danis, E. P., D’Antonio, M. A., Cimons, J. M., Yarnell, M. C., Kedl, R. M., Kohler, M. E., Scott-Browne, J. P., & Fry, T. J. (2025) · Nature Immunology · doi:10.1038/s41590-024-02034-1 · Cited by 17
Self-citationCheng, Y., Shao, Z., Chen, L., Zheng, Q., Zhang, Q., Ding, W., Zhang, M., Yu, Q., & Gao, D. (2020) · Immunology Letters · doi:10.1016/j.imlet.2020.11.004 · Cited by 20
How Can We Engineer CAR T Cells to Overcome Resistance?
Glover, M., Avraamides, S., & Maher, J. F. (2021) · Biologics · doi:10.2147/btt.s252568 · Cited by 19
“97 Engineering CAR T cells to overexpress c-Jun shifts the balance in favour of the formation of proinflammatory c-Jun/c-Fos heterodimers, resulting in reduced terminal differentiation, increased expansion and improved anti-tumour responses against both solid tumour and leukemic xenograft models.97 NFAT is a transcrip…”
BackgroundInfluentialWeber, E. W., Lynn, R. C., Parker, K. R., Anbunathan, H., Lattin, J., Sotillo, E., Good, Z., Malipatlolla, M., Xu, P., Vandris, P., et al. (2020) · doi:10.1101/2020.01.26.920496 · Cited by 18
“…which is associated with a progenitor exhausted cell population that retains anti-tumor functionality and is responsive to checkpoint blockade (Chen et al., 2019c; Im et al., 2016; Jadhav et al., 2019; Utzschneider et al., 2016), was similar in both Always ON and RestedD7-11 conditions and…”
BackgroundInfluentialImmune Dysregulation in Chronic Obstructive Pulmonary Disease
Pang, X., & Liu, X. (2024) · Immunological Investigations · doi:10.1080/08820139.2024.2334296 · Cited by 20
“…regulator in the nucleus and is involved in a variety of biological processes including inflammation, cell proliferation, and apoptosis (J. Chen et al., 2019), cigarette smoke extracts (CSE) increased the overall expression of Nur77 in airway epithelial cells, translocated Nur77 to the…”
BackgroundHeidari‐Foroozan, M., Rezalotfi, A., & Rezaei, N. (2024) · International Reviews of Immunology · doi:10.1080/08830185.2024.2401352 · Cited by 19
“Chen et al. demonstrated that the combination of CAR-T therapy with blockade of NR4A2 stimulates a more robust T cell response and improves the efficacy of the treatment [129].”
Li, J., Jiang, Y., Ma, M., Wang, L., Jing, M., Yang, Z., Zhang, M., Chen, K., & Fan, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06138-6 · Cited by 19
Yoshimura, A., Aki, D., & Ito, M. (2021) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.97.016 · Cited by 19
Self-citationResistance and recurrence of malignancies after CAR-T cell therapy
Zeng, W., & Zhang, P. (2021) · Experimental Cell Research · doi:10.1016/j.yexcr.2021.112971 · Cited by 18
The TOX subfamily: all-round players in the immune system
Han, J., Wan, M., Ma, Z., & He, P. (2022) · Clinical & Experimental Immunology · doi:10.1093/cei/uxac037 · Cited by 18
Application of ATAC-seq in tumor-specific T cell exhaustion
Chen, C., Liu, J., Chen, Y., Lin, A., Mou, W., Zhu, L., Yang, T., Cheng, Q., Zhang, J., & Luo, P. (2022) · Cancer Gene Therapy · doi:10.1038/s41417-022-00495-w · Cited by 19
“The NR4A family members NR4A1 and NR4A2 are up-regulated in CD8+ TILs of human melanoma and metastatic melanoma [30, 81–83].”
BackgroundInfluentialJiménez-Fernández, M., Rodrı́guez, C., Cañes, L., Ballester‐Servera, C., Vara, A., Requena, S., de la Fuente, H., Martínez‐González, J., & Sánchez‐Madrid, F. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04481-1 · Cited by 18
Construction of CAR-T cells targeting TM4SF1 and its anti-tumor capacity in ovarian cancer
Shen, Y., Liu, G., Zhang, Q., Tian, X., Ouyang, L., & Zhang, L. (2023) · Immunology Letters · doi:10.1016/j.imlet.2023.01.011 · Cited by 17
The transcription factor IRF4 determines the anti-tumor immunity of CD8+ T cells
Yan, H., Dai, Y., Zhang, X., Zhang, H., Xiao, X., Fu, J., Zou, D., Yu, A., Jiang, T., Li, X. C., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108087 · Cited by 17
Strategies to Overcome Hurdles in Cancer Immunotherapy
Kim, J. H., Lee, B. J., Moon, S., Lee, H., Lee, J., Kim, B., Jung, K., Seo, H., & Chung, Y. (2024) · Biomaterials Research · doi:10.34133/bmr.0080 · Cited by 19
“This panel exemplifies the advancements in CAR T therapy aimed at enhancing specificity, efficacy, and long-term immune memory in cancer treatment. thereby strengthening their persistence and functional capabilities [33–35].”
Self-citationNew targets and technologies for CAR-T cells
Freitag, F., Maucher, M., Riester, Z., & Hudecek, M. (2020) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000653 · Cited by 20
Improving CAR T-cells: The next generation
Marple, A., Bonifant, C. L., & Shah, N. N. (2020) · Seminars in Hematology · doi:10.1053/j.seminhematol.2020.07.002 · Cited by 18
Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies
Shen, C., Zhang, Z., & Zhang, Y. (2020) · BioMed Research International · doi:10.1155/2020/8765028 · Cited by 18
“Recent studies showed that NR4A-knockout CAR-T cells had low expression of inhibitory receptors and reduced tumor growth [77].”
Background
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
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
