{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T16:07:07Z","timestamp":1791734827133,"version":"4.3.4"},"reference-count":107,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T00:00:00Z","timestamp":1686182400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokushima Bunri University"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The suppression of excessive immune responses is necessary to prevent injury to the body, but it also allows cancer cells to escape immune responses and proliferate. Programmed cell death 1 (PD-1) is a co-inhibitory molecule that is present on T cells and is the receptor for programmed cell death ligand 1 (PD-L1). The binding of PD-1 to PD-L1 leads to the inhibition of the T cell receptor signaling cascade. PD-L1 has been found to be expressed in many types of cancers, such as lung, ovarian, and breast cancer, as well as glioblastoma. Furthermore, PD-L1 mRNA is widely expressed in normal peripheral tissues including the heart, skeletal muscle, placenta, lungs, thymus, spleen, kidney, and liver. The expression of PD-L1 is upregulated by proinflammatory cytokines and growth factors via a number of transcription factors. In addition, various nuclear receptors, such as androgen receptor, estrogen receptor, peroxisome-proliferator-activated receptor \u03b3, and retinoic-acid-related orphan receptor \u03b3, also regulate the expression of PD-L1. This review will focus on the current knowledge of the regulation of PD-L1 expression by nuclear receptors.<\/jats:p>","DOI":"10.3390\/ijms24129891","type":"journal-article","created":{"date-parts":[[2023,6,8]],"date-time":"2023-06-08T03:29:48Z","timestamp":1686194988000},"page":"9891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Regulation of PD-L1 Expression by Nuclear Receptors"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-483X","authenticated-orcid":false,"given":"Yoshimitsu","family":"Kiriyama","sequence":"first","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan"},{"name":"Institute of Neuroscience, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2352-8716","authenticated-orcid":false,"given":"Hiromi","family":"Nochi","sequence":"additional","affiliation":[{"name":"Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 769-2193, Kagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1016\/j.it.2020.09.006","article-title":"The Role of CD8 Downregulation during Thymocyte Differentiation","volume":"41","author":"Nomura","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/nri3405","article-title":"Molecular mechanisms of T cell co-stimulation and co-inhibition","volume":"13","author":"Chen","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3887","DOI":"10.1002\/j.1460-2075.1992.tb05481.x","article-title":"Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death","volume":"11","author":"Ishida","year":"1992","journal-title":"EMBO J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1084\/jem.192.7.1027","article-title":"Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation","volume":"192","author":"Freeman","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/85330","article-title":"PD-L2 is a second ligand for PD-1 and inhibits T cell activation","volume":"2","author":"Latchman","year":"2001","journal-title":"Nat. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1038\/70932","article-title":"B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion","volume":"5","author":"Dong","year":"1999","journal-title":"Nat. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1158\/1535-7163.MCT-14-0983","article-title":"PD-L1 Expression as a Predictive Biomarker in Cancer Immunotherapy","volume":"14","author":"Patel","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bocanegra, A., Blanco, E., Fernandez-Hinojal, G., Arasanz, H., Chocarro, L., Zuazo, M., Morente, P., Vera, R., Escors, D., and Kochan, G. (2020). PD-L1 in Systemic Immunity: Unraveling Its Contribution to PD-1\/PD-L1 Blockade Immunotherapy. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21165918"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12943-018-0928-4","article-title":"Role of the tumor microenvironment in PD-L1\/PD-1-mediated tumor immune escape","volume":"18","author":"Jiang","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Papaccio, F., Della Corte, C.M., Viscardi, G., Di Liello, R., Esposito, G., Sparano, F., Ciardiello, F., and Morgillo, F. (2018). HGF\/MET and the Immune System: Relevance for Cancer Immunotherapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113595"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1248\/bpb.b20-00087","article-title":"Induction of PD-L1 by Nitric Oxide via JNK Activation in A172 Glioblastoma Cells","volume":"43","author":"Kiriyama","year":"2020","journal-title":"Biol. Pharm. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s12943-023-01751-9","article-title":"New frontiers in immune checkpoint B7-H3 (CD276) research and drug development","volume":"22","author":"Getu","year":"2023","journal-title":"Mol. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.immuni.2018.03.014","article-title":"Regulation and Function of the PD-L1 Checkpoint","volume":"48","author":"Sun","year":"2018","journal-title":"Immunity"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-021-00431-4","article-title":"Programmed death ligand 1 signals in cancer cells","volume":"22","author":"Kornepati","year":"2022","journal-title":"Nat. Rev. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s41392-018-0022-9","article-title":"The intracellular signalosome of PD-L1 in cancer cells","volume":"3","author":"Escors","year":"2018","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e35190","DOI":"10.7554\/eLife.35190","article-title":"Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen","volume":"7","author":"Shah","year":"2018","journal-title":"Elife"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24095","DOI":"10.1016\/S0021-9258(19)51052-3","article-title":"Requirement for kinase activity of CD4-associated p56lck in antibody-triggered T cell signal transduction","volume":"269","author":"Chu","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1074\/jbc.273.2.729","article-title":"Tandem SH2 domains confer high specificity in tyrosine kinase signaling","volume":"273","author":"Ottinger","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1038\/s41590-018-0131-1","article-title":"Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT","volume":"19","author":"Lo","year":"2018","journal-title":"Nat. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s41232-019-0095-z","article-title":"T cell receptor signaling for gammadeltaT cell development","volume":"39","author":"Muro","year":"2019","journal-title":"Inflamm. Regen."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"13866","DOI":"10.1073\/pnas.231486598","article-title":"PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine","volume":"98","author":"Okazaki","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1038\/s42003-020-0845-0","article-title":"Interaction of SHP-2 SH2 domains with PD-1 ITSM induces PD-1 dimerization and SHP-2 activation","volume":"3","author":"Patsoukis","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1126\/science.aaf1292","article-title":"T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition","volume":"355","author":"Hui","year":"2017","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"104595","DOI":"10.1016\/j.phrs.2019.104595","article-title":"Targeting SHP2 as a promising strategy for cancer immunotherapy","volume":"152","author":"Liu","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Bailly, C., Thuru, X., and Quesnel, B. (2021). Soluble Programmed Death Ligand-1 (sPD-L1): A Pool of Circulating Proteins Implicated in Health and Diseases. Cancers, 13.","DOI":"10.3390\/cancers13123034"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e1091146","DOI":"10.1080\/2162402X.2015.1091146","article-title":"A novel regulation of PD-1 ligands on mesenchymal stromal cells through MMP-mediated proteolytic cleavage","volume":"5","author":"Durand","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_27","first-page":"379","article-title":"Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage","volume":"52","author":"Nakamura","year":"2018","journal-title":"Int. J. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1093\/intimm\/dxz060","article-title":"Matrix metalloproteinases cleave membrane-bound PD-L1 on CD90+ (myo-)fibroblasts in Crohn\u2019s disease and regulate Th1\/Th17 cell responses","volume":"32","author":"Aguirre","year":"2020","journal-title":"Int. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1744980","DOI":"10.1080\/2162402X.2020.1744980","article-title":"ADAM10 and ADAM17 cleave PD-L1 to mediate PD-(L)1 inhibitor resistance","volume":"9","author":"Orme","year":"2020","journal-title":"Oncoimmunology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s00262-019-02437-2","article-title":"Proteolytic processing of PD-L1 by ADAM proteases in breast cancer cells","volume":"69","author":"Romero","year":"2020","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1093\/annonc\/mdv615","article-title":"Regulation of PD-L1: A novel role of pro-survival signalling in cancer","volume":"27","author":"Chen","year":"2016","journal-title":"Ann. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/s13059-021-02331-0","article-title":"PD-L1 lncRNA splice isoform promotes lung adenocarcinoma progression via enhancing c-Myc activity","volume":"22","author":"Qu","year":"2021","journal-title":"Genome Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1007\/s00262-018-2284-z","article-title":"Identification and characterization of an alternative cancer-derived PD-L1 splice variant","volume":"68","author":"Hassounah","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1007\/s00262-018-2282-1","article-title":"A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression","volume":"68","author":"Mahoney","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e50256","DOI":"10.7554\/eLife.50256","article-title":"Soluble PD-L1 generated by endogenous retroelement exaptation is a receptor antagonist","volume":"8","author":"Ng","year":"2019","journal-title":"Elife"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1158\/2326-6066.CIR-16-0329","article-title":"Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade","volume":"5","author":"Zhou","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1084\/jem.20180870","article-title":"Secreted PD-L1 variants mediate resistance to PD-L1 blockade therapy in non-small cell lung cancer","volume":"216","author":"Gong","year":"2019","journal-title":"J. Exp. Med."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Chavez-Galan, L., Ruiz, A., Martinez-Espinosa, K., Aguilar-Duran, H., Torres, M., Falfan-Valencia, R., Perez-Rubio, G., Selman, M., and Buendia-Roldan, I. (2022). Circulating Levels of PD-L1, TIM-3 and MMP-7 Are Promising Biomarkers to Differentiate COVID-19 Patients That Require Invasive Mechanical Ventilation. Biomolecules, 12.","DOI":"10.3390\/biom12030445"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"97671","DOI":"10.18632\/oncotarget.18311","article-title":"Soluble PD-1 and PD-L1: Predictive and prognostic significance in cancer","volume":"8","author":"Zhu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13049","DOI":"10.1111\/sji.13049","article-title":"Serum-soluble PD-L1 may be a potential diagnostic biomarker in sepsis","volume":"94","author":"Sun","year":"2021","journal-title":"Scand. J. Immunol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e20065","DOI":"10.1097\/MD.0000000000020065","article-title":"Soluble PD-L1: A potential immune marker for HIV-1 infection and virological failure","volume":"99","author":"Rodriguez","year":"2020","journal-title":"Medicine"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1111\/sji.12509","article-title":"Serum sPD-L1, Upregulated in Sepsis, May Reflect Disease Severity and Clinical Outcomes in Septic Patients","volume":"85","author":"Liu","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1097\/SHK.0000000000001228","article-title":"Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis","volume":"52","author":"Kawamoto","year":"2019","journal-title":"Shock"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"88360","DOI":"10.18632\/oncotarget.21729","article-title":"High-affinity human PD-L1 variants attenuate the suppression of T cell activation","volume":"8","author":"Liang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1002\/JLB.1A0420-012RR","article-title":"Trophoblast-secreted soluble-PD-L1 modulates macrophage polarization and function","volume":"108","author":"Zhang","year":"2020","journal-title":"J. Leukoc. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3389\/fimmu.2019.00086","article-title":"Elevated Soluble PD-L1 in Pregnant Women\u2019s Serum Suppresses the Immune Reaction","volume":"10","author":"Okuyama","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e12795","DOI":"10.1111\/aji.12795","article-title":"Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy","volume":"79","author":"Enninga","year":"2018","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1007\/s00262-022-03176-7","article-title":"The nuclear transportation of PD-L1 and the function in tumor immunity and progression","volume":"71","author":"Qu","year":"2022","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/s41571-022-00601-9","article-title":"Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics","volume":"19","author":"Yamaguchi","year":"2022","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1064","DOI":"10.1038\/s41556-020-0562-4","article-title":"Acetylation-dependent regulation of PD-L1 nuclear translocation dictates the efficacy of anti-PD-1 immunotherapy","volume":"22","author":"Gao","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1038\/s41418-020-00651-5","article-title":"KPNB1-mediated nuclear translocation of PD-L1 promotes non-small cell lung cancer cell proliferation via the Gas6\/MerTK signaling pathway","volume":"28","author":"Du","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1038\/s41556-020-0575-z","article-title":"PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis","volume":"22","author":"Hou","year":"2020","journal-title":"Nat. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Pan, P., and Chen, X. (2020). Nuclear Receptors as Potential Therapeutic Targets for Myeloid Leukemia. Cells, 9.","DOI":"10.3390\/cells9091921"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1876","DOI":"10.1002\/pro.3496","article-title":"The nuclear receptor superfamily: A structural perspective","volume":"27","author":"Weikum","year":"2018","journal-title":"Protein Sci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Porter, B.A., Ortiz, M.A., Bratslavsky, G., and Kotula, L. (2019). Structure and Function of the Nuclear Receptor Superfamily and Current Targeted Therapies of Prostate Cancer. Cancers, 11.","DOI":"10.20944\/preprints201910.0303.v1"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","article-title":"The nuclear receptor superfamily: The second decade","volume":"83","author":"Mangelsdorf","year":"1995","journal-title":"Cell"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/aps.2014.18","article-title":"Androgen receptor: Structure, role in prostate cancer and drug discovery","volume":"36","author":"Tan","year":"2015","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"38087","DOI":"10.1074\/jbc.M203313200","article-title":"Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells","volume":"277","author":"Ueda","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"10854","DOI":"10.18632\/oncotarget.2536","article-title":"Stromal TGF-beta signaling induces AR activation in prostate cancer","volume":"5","author":"Yang","year":"2014","journal-title":"Oncotarget"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1210\/me.2014-1315","article-title":"Minireview: Tipping the balance: Ligand-independent activation of steroid receptors","volume":"29","author":"Bennesch","year":"2015","journal-title":"Mol. Endocrinol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11466","DOI":"10.18632\/aging.103231","article-title":"Androgen receptor affects the response to immune checkpoint therapy by suppressing PD-L1 in hepatocellular carcinoma","volume":"12","author":"Jiang","year":"2020","journal-title":"Aging"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"663130","DOI":"10.3389\/fcell.2021.663130","article-title":"Androgen Activity Is Associated with PD-L1 Downregulation in Thyroid Cancer","volume":"9","author":"Dadafarin","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1988","DOI":"10.1038\/s41417-022-00506-w","article-title":"Targeting the androgen receptor to enhance NK cell killing efficacy in bladder cancer by modulating ADAR2\/circ_0001005\/PD-L1 signaling","volume":"29","author":"Liu","year":"2022","journal-title":"Cancer Gene Ther."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.omtn.2019.04.011","article-title":"Emerging Epigenetic Regulation of Circular RNAs in Human Cancer","volume":"16","author":"Wu","year":"2019","journal-title":"Mol. Ther. Nucleic Acids"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41580-018-0045-7","article-title":"Regulation of microRNA function in animals","volume":"20","author":"Gebert","year":"2019","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5241","DOI":"10.1038\/ncomms6241","article-title":"Metastasis is regulated via microRNA-200\/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression","volume":"5","author":"Chen","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Klepsch, V., Siegmund, K., and Baier, G. (2021). Emerging Next-Generation Target for Cancer Immunotherapy Research: The Orphan Nuclear Receptor NR2F6. Cancers, 13.","DOI":"10.3390\/cancers13112600"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"13","DOI":"10.31083\/j.fbl2801013","article-title":"New Insights into the Diverse Functions of the NR2F Nuclear Orphan Receptor Family","volume":"28","author":"Sajinovic","year":"2023","journal-title":"Front. Biosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1038\/s41467-018-04004-2","article-title":"Nuclear receptor NR2F6 inhibition potentiates responses to PD-L1\/PD-1 cancer immune checkpoint blockade","volume":"9","author":"Klepsch","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s12964-019-0454-z","article-title":"Targeting the orphan nuclear receptor NR2F6 in T cells primes tumors for immune checkpoint therapy","volume":"18","author":"Klepsch","year":"2020","journal-title":"Cell Commun. Signal."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1210\/er.2018-00087","article-title":"Estrogen Receptors: New Directions in the New Millennium","volume":"39","author":"Hewitt","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1210\/endo.142.8.8333","article-title":"Ligand-independent activation of pituitary ER: Dependence on PKA-stimulated pathways","volume":"142","author":"Schreihofer","year":"2001","journal-title":"Endocrinology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1101\/gad.568410","article-title":"CARM1 mediates the ligand-independent and tamoxifen-resistant activation of the estrogen receptor alpha by cAMP","volume":"24","author":"Carascossa","year":"2010","journal-title":"Genes Dev."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1002\/1878-0261.12654","article-title":"Programmed death-ligand 1 gene expression is a prognostic marker in early breast cancer and provides additional prognostic value to 21-gene and 70-gene signatures in estrogen receptor-positive disease","volume":"14","author":"Zerdes","year":"2020","journal-title":"Mol. Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.bbrc.2018.09.005","article-title":"ERalpha is a negative regulator of PD-L1 gene transcription in breast cancer","volume":"505","author":"Liu","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/1878-0261.13083","article-title":"Prolonged estrogen deprivation triggers a broad immunosuppressive phenotype in breast cancer cells","volume":"16","author":"Huhn","year":"2022","journal-title":"Mol. Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"582863","DOI":"10.3389\/fonc.2020.582863","article-title":"Estrogen Receptor Downregulates Expression of PD-1\/PD-L1 and Infiltration of CD8(+) T Cells by Inhibiting IL-17 Signaling Transduction in Breast Cancer","volume":"10","author":"Shuai","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"7614","DOI":"10.18632\/oncotarget.13819","article-title":"Targeting of interleukin (IL)-17A inhibits PDL1 expression in tumor cells and induces anticancer immunity in an estrogen receptor-negative murine model of breast cancer","volume":"8","author":"Ma","year":"2017","journal-title":"Oncotarget"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Soliman, H., Khalil, F., and Antonia, S. (2014). PD-L1 expression is increased in a subset of basal type breast cancer cells. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0088557"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"215780","DOI":"10.1016\/j.canlet.2022.215780","article-title":"Combination treatment with 17beta-estradiol and anti-PD-L1 suppresses MC38 tumor growth by reducing PD-L1 expression and enhancing M1 macrophage population in MC38 colon tumor model","volume":"543","author":"Song","year":"2022","journal-title":"Cancer Lett."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Kiriyama, Y., and Nochi, H. (2021). Physiological Role of Bile Acids Modified by the Gut Microbiome. Microorganisms, 10.","DOI":"10.3390\/microorganisms10010068"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3892\/ijo.2022.5330","article-title":"High farnesoid X receptor expression predicts favorable clinical outcomes in PD-L1(low\/negative) non-small cell lung cancer patients receiving anti-PD-1-based chemo-immunotherapy","volume":"60","author":"Wang","year":"2022","journal-title":"Int. J. Oncol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1158\/2326-6066.CIR-17-0672","article-title":"Farnesoid X Receptor Constructs an Immunosuppressive Microenvironment and Sensitizes FXR(high)PD-L1(low) NSCLC to Anti-PD-1 Immunotherapy","volume":"7","author":"You","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"711448","DOI":"10.3389\/fonc.2021.711448","article-title":"Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma","volume":"11","author":"Gong","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/nrm.2016.152","article-title":"Glucocorticoid receptor control of transcription: Precision and plasticity via allostery","volume":"18","author":"Weikum","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"100687","DOI":"10.1016\/j.jbc.2021.100687","article-title":"Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era","volume":"296","author":"Gerber","year":"2021","journal-title":"J. Biol. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"7041","DOI":"10.1038\/s41467-021-27349-7","article-title":"Glucocorticoid receptor regulates PD-L1 and MHC-I in pancreatic cancer cells to promote immune evasion and immunotherapy resistance","volume":"12","author":"Deng","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"5002","DOI":"10.1038\/s41388-021-01897-0","article-title":"Dexamethasone suppresses immune evasion by inducing GR\/STAT3 mediated downregulation of PD-L1 and IDO1 pathways","volume":"40","author":"Xiang","year":"2021","journal-title":"Oncogene"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"624122","DOI":"10.3389\/fendo.2020.624122","article-title":"Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology","volume":"11","author":"Odagiu","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"972984","DOI":"10.3389\/fonc.2022.972984","article-title":"Therapeutic potential of NR4A1 in cancer: Focus on metabolism","volume":"12","author":"Deng","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1210\/me.2014-1102","article-title":"Diindolylmethane analogs bind NR4A1 and are NR4A1 antagonists in colon cancer cells","volume":"28","author":"Lee","year":"2014","journal-title":"Mol. Endocrinol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1158\/0008-5472.CAN-19-2314","article-title":"A Bis-Indole-Derived NR4A1 Antagonist Induces PD-L1 Degradation and Enhances Antitumor Immunity","volume":"80","author":"Karki","year":"2020","journal-title":"Cancer Res."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Karki, K., Mohankumar, K., Schoeller, A., Martin, G., Shrestha, R., and Safe, S. (2021). NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth. Cancers, 13.","DOI":"10.3390\/cancers13112682"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/s41586-019-0979-8","article-title":"Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction","volume":"567","author":"Liu","year":"2019","journal-title":"Nature"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Brunmeir, R., and Xu, F. (2018). Functional Regulation of PPARs through Post-Translational Modifications. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19061738"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Zhao, B., Xin, Z., Ren, P., and Wu, H. (2022). The Role of PPARs in Breast Cancer. Cells, 12.","DOI":"10.3390\/cells12010130"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1906500","DOI":"10.1080\/2162402X.2021.1906500","article-title":"PPARgamma induces PD-L1 expression in MSS+ colorectal cancer cells","volume":"10","author":"Gutting","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"e1500107","DOI":"10.1080\/2162402X.2018.1500107","article-title":"Adipose PD-L1 Modulates PD-1\/PD-L1 Checkpoint Blockade Immunotherapy Efficacy in Breast Cancer","volume":"7","author":"Wu","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e003","DOI":"10.1621\/nrs.07003","article-title":"Retinoid-related orphan receptors (RORs): Critical roles in development, immunity, circadian rhythm, and cellular metabolism","volume":"7","author":"Jetten","year":"2009","journal-title":"Nucl. Recept. Signal."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1039\/D0NP00047G","article-title":"Natural products as modulators of retinoic acid receptor-related orphan receptors (RORs)","volume":"38","author":"Ladurner","year":"2021","journal-title":"Nat. Prod. Rep."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.3389\/fimmu.2018.01187","article-title":"Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis","volume":"9","author":"Fan","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2604","DOI":"10.1158\/0008-5472.CAN-18-3842","article-title":"Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1\/ITGB6\/STAT3 Signaling Axis in Bladder Cancer","volume":"79","author":"Cao","year":"2019","journal-title":"Cancer Res."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"bqab184","DOI":"10.1210\/endocr\/bqab184","article-title":"TLX, an Orphan Nuclear Receptor with Emerging Roles in Physiology and Disease","volume":"162","author":"Nelson","year":"2021","journal-title":"Endocrinology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e2023784119","DOI":"10.1073\/pnas.2023784119","article-title":"Oleic acid is an endogenous ligand of TLX\/NR2E1 that triggers hippocampal neurogenesis","volume":"119","author":"Kandel","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e001937","DOI":"10.1136\/jitc-2020-001937","article-title":"Orphan nuclear receptor TLX promotes immunosuppression via its transcriptional activation of PD-L1 in glioma","volume":"9","author":"Zhou","year":"2021","journal-title":"J. Immunother. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1172\/JCI88887","article-title":"The vitamin D receptor: Contemporary genomic approaches reveal new basic and translational insights","volume":"127","author":"Pike","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"20657","DOI":"10.1074\/jbc.M117.793885","article-title":"Hormonal vitamin D up-regulates tissue-specific PD-L1 and PD-L2 surface glycoprotein expression in humans but not mice","volume":"292","author":"Dimitrov","year":"2017","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9891\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:50:39Z","timestamp":1760125839000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/12\/9891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,8]]},"references-count":107,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["ijms24129891"],"URL":"https:\/\/doi.org\/10.3390\/ijms24129891","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,8]]}}}