{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:20:44Z","timestamp":1791656444560,"version":"4.3.4"},"reference-count":54,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T00:00:00Z","timestamp":1652659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometriosis is a gynaecological disease defined by the growth of endometrium-like tissue outside the uterus. The disease is present in approximately 5\u201310% of women of reproductive age and causes pelvic pain and infertility. The pathophysiology is not completely understood, but retrograde menstruation and deficiency in natural killer (NK) cells that clear endometriotic cells in the peritoneal cavity play an important role. Nowadays, hormonal therapy and surgery to remove endometriosis lesions are used as treatment. However, these therapies do not work for all patients, and hormonal therapy prevents patients from getting pregnant. Therefore, new treatment strategies should be developed. Since the cytotoxicity of NK cells is decreased in endometriosis, we performed a literature search into the possibility of NK cell therapy. Available treatment options include the inhibition of receptor\u2013ligand interaction for KIR2DL1, NKG2A, LILRB1\/2, and PD-1\/PD-L1; inhibition of TGF-\u03b2; stimulation of NK cells with IL-2; and mycobacterial treatment with BCG. In preclinical work, these therapies show promising results but unfortunately have side effects, which have not specifically been studied in endometriosis patients. Before NK cell treatment can be used in the clinic, more research is needed.<\/jats:p>","DOI":"10.3390\/ijms23105539","type":"journal-article","created":{"date-parts":[[2022,5,16]],"date-time":"2022-05-16T13:06:23Z","timestamp":1652706383000},"page":"5539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["The Promises of Natural Killer Cell Therapy in Endometriosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9838-0977","authenticated-orcid":false,"given":"Janneke","family":"Hoogstad-van Evert","sequence":"first","affiliation":[{"name":"Amphia Hospital, 4838 Breda, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romy","family":"Paap","sequence":"additional","affiliation":[{"name":"Center of Translational Immunology, University Medical Center, 3553 Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annemiek","family":"Nap","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Radboudumc, 6524 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3113-6587","authenticated-orcid":false,"given":"Renate","family":"van der Molen","sequence":"additional","affiliation":[{"name":"Laboratory Sciences, Radboudumc, 6524 Nijmegen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/aji.12408","article-title":"Natural Killer Cells: Key Players in Endometriosis","volume":"74","author":"Thiruchelvam","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1507\/endocrj.K08E-067","article-title":"Molecular and cellular mechanisms for differentiation and regeneration of the uterine endometrium","volume":"55","author":"Maruyama","year":"2008","journal-title":"Endocr. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.fertnstert.2012.06.029","article-title":"Pathogenesis and pathophysiology of endometriosis","volume":"98","author":"Burney","year":"2012","journal-title":"Fertil. Steril."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1093\/humupd\/dmq050","article-title":"Chronic pelvic pain and endometriosis: Translational evidence of the relationship and implications","volume":"17","author":"Stratton","year":"2011","journal-title":"Hum. Reprod. Update"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.fertnstert.2011.05.090","article-title":"Impact of endometriosis on quality of life and work productivity: A multicenter study across ten countries","volume":"96","author":"Nnoaham","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_6","first-page":"e3361","article-title":"The Clinical Anatomy of Endometriosis: A Review","volume":"10","author":"Alimi","year":"2018","journal-title":"Cureus"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1097\/AOG.0000000000002469","article-title":"Clinical Management of Endometriosis","volume":"131","author":"Falcone","year":"2018","journal-title":"Obstet. Gynecol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1210\/er.2018-00242","article-title":"Endometriosis","volume":"40","author":"Bulun","year":"2019","journal-title":"Endocr. Rev."},{"key":"ref_9","first-page":"349","article-title":"Endometriosis still a challenge","volume":"7","author":"Mehedintu","year":"2014","journal-title":"J. Med. Life"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bpobgyn.2018.01.010","article-title":"Immunology of endometriosis","volume":"50","author":"Riccio","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/jog.13559","article-title":"Involvement of immune cells in the pathogenesis of endometriosis","volume":"44","author":"Izumi","year":"2018","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1177\/1933719115592713","article-title":"Pathogenetic Mechanisms of Deep Infiltrating Endometriosis","volume":"22","author":"Tosti","year":"2015","journal-title":"Reprod. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1095\/biolreprod66.1.1","article-title":"Extracellular matrix-dependent regulation of Fas ligand expression in human endometrial stromal cells","volume":"66","author":"Selam","year":"2002","journal-title":"Biol. Reprod."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1096\/fj.07-9034com","article-title":"Dendritic cells support angiogenesis and promote lesion growth in a murine model of endometriosis","volume":"22","author":"Fainaru","year":"2008","journal-title":"FASEB J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.rbmo.2013.12.011","article-title":"The development of endometriosis in a murine model is dependent on the presence of dendritic cells","volume":"28","author":"Pencovich","year":"2014","journal-title":"Reprod. Biomed. Online"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1177\/1933719114525267","article-title":"Dendritic cells attenuate the early establishment of endometriosis-like lesions in a murine model","volume":"21","author":"Stanic","year":"2014","journal-title":"Reprod. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.jri.2017.04.003","article-title":"What do we know about regulatory T cells and endometriosis? A systematic review","volume":"120","author":"Malvezzi","year":"2017","journal-title":"J. Reprod. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"103119","DOI":"10.1016\/j.jri.2020.103119","article-title":"Higher frequency of circulating, but not tissue regulatory T cells in patients with endometriosis","volume":"139","author":"Delbandi","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2916070","DOI":"10.1155\/2016\/2916070","article-title":"Decreased Cytotoxicity of Peripheral and Peritoneal Natural Killer Cell in Endometriosis","volume":"2016","author":"Jeung","year":"2016","journal-title":"BioMed Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"467","DOI":"10.3389\/fimmu.2017.00467","article-title":"Uterine Natural Killer Cells: Functional Distinctions and Influence on Pregnancy in Humans and Mice","volume":"8","author":"Gaynor","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.8755-8920.2000.430405.x","article-title":"Menstrual cycle dependent fluctuations in NK and T-lymphocyte subsets from non-pregnant human endometrium","volume":"43","author":"Flynn","year":"2000","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"671201","DOI":"10.3389\/fimmu.2021.671201","article-title":"Identification and Validation of the Signatures of Infiltrating Immune Cells in the Eutopic Endometrium Endometria of Women With Endometriosis","volume":"12","author":"Wu","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_23","first-page":"564","article-title":"The endometrial immune environment of women with endometriosis","volume":"25","author":"Houshdaran","year":"2019","journal-title":"Hum. Reprod. Update"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.placenta.2017.03.001","article-title":"Uterine NK cells and macrophages in pregnancy","volume":"56","author":"Faas","year":"2017","journal-title":"Placenta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000052854","article-title":"Intercellular adhesion molecule-1 and hepatocyte growth factor in human endometriosis: Original investigation and a review of literature","volume":"47","author":"Fukaya","year":"1999","journal-title":"Gynecol. Obstet. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0015-0282(01)02964-8","article-title":"Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis","volume":"77","author":"Maeda","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19352","DOI":"10.1002\/jcp.28657","article-title":"NK cells: An attractive candidate for cancer therapy","volume":"234","author":"Valipour","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1016\/j.ygyno.2020.03.020","article-title":"Harnessing natural killer cells for the treatment of ovarian cancer","volume":"157","author":"Bekkers","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.2217\/imt.11.131","article-title":"Use of allogeneic NK cells for cancer immunotherapy","volume":"3","author":"Geller","year":"2011","journal-title":"Immunotherapy"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1007\/s12026-017-8982-3","article-title":"IL-2 mediates NK cell proliferation but not hyperactivity","volume":"66","author":"Sharma","year":"2018","journal-title":"Immunol. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1002\/ijgo.12576","article-title":"Systematic review and meta-analysis of complementary treatments for women with symptomatic endometriosis","volume":"143","author":"Mira","year":"2018","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Sciezynska, A., Komorowski, M., Soszynska, M., and Malejczyk, J. (2019). NK Cells as Potential Targets for Immunotherapy in Endometriosis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8091468"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/j.1600-0897.2005.00271.x","article-title":"Expression of inhibitory-motif killer immunoglobulin-like receptor, KIR2DL1, is increased in natural killer cells from women with pelvic endometriosis","volume":"53","author":"Matsuoka","year":"2005","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1007\/s00438-017-1404-3","article-title":"The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis","volume":"293","author":"Bylinska","year":"2018","journal-title":"Mol. Genet. Genom."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/j.fertnstert.2007.05.018","article-title":"Increased frequency of human leukocyte antigen-E inhibitory receptor CD94\/NKG2A-expressing peritoneal natural killer cells in patients with endometriosis","volume":"89","author":"Galandrini","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/09513590.2018.1519787","article-title":"Expression of programmed death-1 (PD-1) and its ligand PD-L1 is upregulated in endometriosis and promoted by 17beta-estradiol","volume":"35","author":"Wu","year":"2019","journal-title":"Gynecol. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.imlet.2018.10.011","article-title":"The involvement of multifunctional TGF-beta and related cytokines in pathogenesis of endometriosis","volume":"201","author":"Sikora","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_38","first-page":"3269","article-title":"Involvement of angiotensin II receptor type 1\/NF-kappaB signaling in the development of endometriosis","volume":"20","author":"Zhang","year":"2020","journal-title":"Exp. Ther. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1111\/jog.12558","article-title":"Regression of experimental endometriotic implants in a rat model with the angiotensin II receptor blocker losartan","volume":"41","author":"Cakmak","year":"2015","journal-title":"J. Obstet. Gynaecol. Res."},{"key":"ref_40","first-page":"42","article-title":"Angiotensin II Receptor Antagonism Reduces Transforming Growth Factor Beta and Smad Signaling in Thoracic Aortic Aneurysm","volume":"13","author":"Nataatmadja","year":"2013","journal-title":"Ochsner. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.jri.2006.12.001","article-title":"Intraperitoneal recombinant interleukin-2 activates leukocytes in rat endometriosis","volume":"74","author":"Velasco","year":"2007","journal-title":"J. Reprod. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1886","DOI":"10.1093\/humrep\/deh340","article-title":"Increase in peripheral blood mononuclear cell (PBMC)- and CD56+ cell-mediated killing of endometrial stromal cells by mycobacteria; a possible role in endometriosis immunotherapy?","volume":"19","author":"Clayton","year":"2004","journal-title":"Hum. Reprod."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6392","DOI":"10.4049\/jimmunol.180.9.6392","article-title":"Blocking NK cell inhibitory self-recognition promotes antibody-dependent cellular cytotoxicity in a model of anti-lymphoma therapy","volume":"180","author":"Binyamin","year":"2008","journal-title":"J. Immunol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/bs.ai.2015.04.001","article-title":"HLA-G: An Immune Checkpoint Molecule","volume":"127","author":"Carosella","year":"2015","journal-title":"Adv. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1111\/tan.12427","article-title":"New insights into HLA-G mediated tolerance","volume":"84","author":"Amodio","year":"2014","journal-title":"Tissue Antigens"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.cell.2018.10.014","article-title":"Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells","volume":"175","author":"Andre","year":"2018","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6052","DOI":"10.1158\/1078-0432.CCR-19-0298","article-title":"Dose-Ranging and Cohort-Expansion Study of Monalizumab (IPH2201) in Patients with Advanced Gynecologic Malignancies: A Trial of the Canadian Cancer Trials Group (CCTG): IND221","volume":"25","author":"Tinker","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4863","DOI":"10.21037\/jtd.2017.11.105","article-title":"Why anti-PD1\/PDL1 therapy is so effective? Another piece in the puzzle","volume":"9","author":"Marchetti","year":"2017","journal-title":"J. Thorac. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"vii7","DOI":"10.1093\/rheumatology\/kez418","article-title":"Toxicities associated with checkpoint inhibitors-an overview","volume":"58","author":"Spiers","year":"2019","journal-title":"Rheumatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3109\/08977194.2011.595411","article-title":"Exploring anti-TGF-beta therapies in cancer and fibrosis","volume":"29","author":"Hawinkels","year":"2011","journal-title":"Growth Factors"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2934","DOI":"10.2174\/13816128113199990591","article-title":"TGF-beta signaling in cancer treatment","volume":"20","author":"Fabregat","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/nrrheum.2009.26","article-title":"Transforming growth factor beta as a therapeutic target in systemic sclerosis","volume":"5","author":"Varga","year":"2009","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"e1163462","DOI":"10.1080\/2162402X.2016.1163462","article-title":"Role of IL-2 in cancer immunotherapy","volume":"5","author":"Jiang","year":"2016","journal-title":"Oncoimmunology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1159\/000292556","article-title":"Lymphokine-activated killer activity in women with endometriosis","volume":"37","author":"Oosterlynck","year":"1994","journal-title":"Gynecol. Obstet. Investig."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5539\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:11:15Z","timestamp":1760137875000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/10\/5539"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,16]]},"references-count":54,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23105539"],"URL":"https:\/\/doi.org\/10.3390\/ijms23105539","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,16]]}}}