{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T01:52:09Z","timestamp":1791856329950,"version":"4.3.4"},"reference-count":58,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"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>Successful embryo implantation requires dynamic, bidirectional communication between a developmentally competent blastocyst and a receptive endometrium, integrating hormonal, molecular, and immunologic signals. Increasing evidence indicates that endometrial receptivity is critically dependent on a specialized immune microenvironment that supports trophoblast invasion while maintaining maternal tolerance. This review synthesizes current knowledge on the immunologic regulation of implantation, with emphasis on uterine natural killer (uNK) cells, regulatory T cells (Tregs), macrophages, dendritic cells, and cytokine networks. We further examine intracellular signaling pathways\u2014including JAK\/STAT, PI3K\/AKT, NF-\u03baB, and MAPK\u2014that integrate immune and decidual responses. The bidirectional embryo\u2013endometrium dialogue is explored through embryo-derived mediators such as human chorionic gonadotropin (hCG), cytokines, growth factors, and extracellular vesicles. The endometrium is increasingly recognized as a biosensor of embryo quality, selectively supporting viable embryos. Disruption of this complex communication network is implicated in recurrent implantation failure and early pregnancy loss. Despite substantial mechanistic advances, clinical translation remains limited. Emerging strategies, including immune profiling, microbiome modulation, and extracellular vesicle-based diagnostics, hold promise for precision reproductive medicine.<\/jats:p>","DOI":"10.3390\/ijms27104588","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T14:12:54Z","timestamp":1779286374000},"page":"4588","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of Immunologic Factors in Endometrial Receptivity: An Embryo\u2013Endometrium Dialogue"],"prefix":"10.3390","volume":"27","author":[{"given":"Evangelia","family":"Panagodimou","sequence":"first","affiliation":[{"name":"Department of Obstetrics & Gynecology, IASO Clinic, 151 23 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ianthi","family":"Terzopoulou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4403-0511","authenticated-orcid":false,"given":"Olga","family":"Triantafyllidou","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Aretaieio Hospital, Medical School of Athens, 115 28 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1519-3776","authenticated-orcid":false,"given":"Georgios","family":"Markantes","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neoklis","family":"Georgopoulos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolaos","family":"Vlahos","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Aretaieio Hospital, Medical School of Athens, 115 28 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9503-8137","authenticated-orcid":false,"given":"George","family":"Adonakis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4738-2582","authenticated-orcid":false,"given":"Apostolos","family":"Kaponis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1111\/j.1749-6632.1986.tb20920.x","article-title":"Uterine receptivity for nidation","volume":"476","author":"Psychoyos","year":"1986","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1210\/er.2003-0020","article-title":"Molecular cues to implantation","volume":"25","author":"Dey","year":"2004","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"104827","DOI":"10.1016\/j.rbmo.2025.104827","article-title":"Resolving recurrent implantation failure","volume":"50","author":"Macklon","year":"2025","journal-title":"Reprod. Biomed. Online"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"hoad023","DOI":"10.1093\/hropen\/hoad023","article-title":"ESHRE good practice recommendations on recurrent implantation failure","volume":"2023","author":"Cimadomo","year":"2023","journal-title":"Hum. Reprod. Open"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1111\/j.1600-0897.2010.00836.x","article-title":"The immune system in pregnancy","volume":"63","author":"Mor","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev-immunol-032712-100003","article-title":"Immunology of the maternal\u2013fetal interface","volume":"31","author":"Erlebacher","year":"2013","journal-title":"Annu. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/aji.12097","article-title":"Adaptive immune responses during pregnancy","volume":"69","author":"Zenclussen","year":"2013","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0165-0378(01)00139-5","article-title":"Adhesion molecules and implantation","volume":"55","author":"Lessey","year":"2002","journal-title":"J. Reprod. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.fertnstert.2010.04.063","article-title":"A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature","volume":"95","author":"Horcahadas","year":"2011","journal-title":"Fertil. Steril."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1189\/jlb.0708395","article-title":"Embryonic implantation: Cytokines, adhesion molecules, and immune cells in establishing an implantation environment","volume":"85","author":"Macklon","year":"2009","journal-title":"J. Leukoc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1146\/annurev-immunol-102119-075119","article-title":"Natural Killer Cells in the Human Uterine Mucosa","volume":"41","author":"Male","year":"2023","journal-title":"Annu. Rev. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/j.1600-0897.1996.tb00041.x","article-title":"Functions of human decidual NK cells","volume":"35","author":"King","year":"1996","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/nm1452","article-title":"Decidual NK cells regulate key developmental processes at the human fetal-maternal interface","volume":"12","author":"Hanna","year":"2006","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.placenta.2009.12.022","article-title":"Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua","volume":"31","author":"Lash","year":"2010","journal-title":"Placenta"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1172\/JCI68107","article-title":"Uterine NK cells: Active regulators at the maternal\u2013fetal interface","volume":"124","author":"Moffett","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1093\/humupd\/dmac006","article-title":"Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: A systematic review and meta-analysis","volume":"28","author":"Greer","year":"2022","journal-title":"Hum. Reprod. Update"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1084\/jem.20041214","article-title":"Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success","volume":"200","author":"Hiby","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nri1570","article-title":"MHC class I molecules and KIRs in human history, health and survival","volume":"5","author":"Parham","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s00251-017-1003-9","article-title":"The role of KIR and HLA interactions in pregnancy complications","volume":"69","author":"Colucci","year":"2017","journal-title":"Immunogenetics"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/humupd\/dmt056","article-title":"Natural killer cells in female infertility and recurrent miscarriage: A systematic review and meta-analysis","volume":"20","author":"Seshadri","year":"2014","journal-title":"Hum. Reprod. Update"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1172\/JCI122182","article-title":"Regulatory T cells in embryo implantation and the immune response to pregnancy","volume":"128","author":"Robertson","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"103165","DOI":"10.1016\/j.jri.2020.103165","article-title":"Uterine CD11c+ cells induce the development of paternal antigen-specific Tregs via seminal plasma priming","volume":"141","author":"Shima","year":"2020","journal-title":"J. Reprod. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13393","DOI":"10.1111\/aji.13393","article-title":"Do endometrial natural killer and regulatory T cells differ in infertile and clinical pregnancy patients? An analysis in patients undergoing frozen embryo transfer cycles","volume":"85","author":"Huber","year":"2021","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nri.2017.64","article-title":"The unique immunological and microbial aspects of pregnancy","volume":"17","author":"Mor","year":"2017","journal-title":"Nat. Rev. Immunol."},{"key":"ref_26","first-page":"3954","article-title":"Uterine DCs are crucial for decidua formation during embryo implantation in mice","volume":"118","author":"Plaks","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"110921","DOI":"10.1016\/j.biopha.2020.110921","article-title":"Dendritic cells in pregnancy and pregnancy-associated diseases","volume":"133","author":"Wei","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1107","DOI":"10.1016\/j.fertnstert.2022.04.023","article-title":"Immune determinants of endometrial receptivity: A biological perspective","volume":"117","author":"Robertson","year":"2022","journal-title":"Fertil. Steril."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/j.1365-2826.2008.01668.x","article-title":"Cytokine Networks and the Regulation of Uterine Function in Pregnancy and Parturition","volume":"20","author":"Orsi","year":"2008","journal-title":"J. Neuroendocrinol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/j.yexcr.2008.07.025","article-title":"HB-EGF: A unique mediator of embryo-uterine interactions during implantation","volume":"315","author":"Lim","year":"2009","journal-title":"Exp. Cell Res."},{"key":"ref_31","first-page":"595","article-title":"The evaluation role of T helper 17 cells in pregnancy and abortion: A molecular and future perspective: Narrative review","volume":"23","author":"Etezadi","year":"2025","journal-title":"Int. J. Reprod. Biomed."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1242\/jcs.00963","article-title":"The JAK\/STAT signaling pathway","volume":"117","author":"Rawlings","year":"2004","journal-title":"J. Cell Sci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Matsuyama, S., Whiteside, S., and Li, S.Y. (2024). Implantation and Decidualization in PCOS: Unraveling the Complexities of Pregnancy. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25021203"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s10863-020-09854-4","article-title":"Key factors mediated by PI3K signaling pathway and related genes in endometrial carcinoma","volume":"52","author":"Liu","year":"2020","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_35","first-page":"203","article-title":"Research Resource: Interactome of Human Embryo Implantation: Identification of Gene Expression Pathways, Regulation, and Integrated Regulatory Networks","volume":"26","author":"Reimand","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e2206000119","DOI":"10.1073\/pnas.2206000119","article-title":"P38\u03b1 MAPK is a gatekeeper of uterine progesterone responsiveness at peri-implantation via Ube3c-mediated PGR degradation","volume":"119","author":"Tang","year":"2022","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1210\/er.2014-1045","article-title":"Cyclic decidualization of the human endometrium in reproductive health and failure","volume":"35","author":"Gellersen","year":"2014","journal-title":"Endocr. Rev."},{"key":"ref_38","first-page":"44","article-title":"Time-series single-cell transcriptomic profiling of luteal-phase endometrium uncovers dynamic characteristics and its dysregulation in recurrent implantation failures","volume":"16","author":"Liu","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1095\/biolreprod.114.122846","article-title":"The endometrium as a sensor of embryo quality","volume":"91","author":"Macklon","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Voros, C., Chatzinikolaou, F., Papadimas, G., Polykalas, S., Koulakmanidis, A.M., Athanasiou, D., Kanaka, V., Kanaka, M., Bananis, K., and Athanasiou, A. (2025). Molecular Crosstalk Between Intrauterine hCG and Endometrial Receptivity: Signalling Pathways, Immune Modulation, and Translational Perspectives in IVF. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27010278"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/humrep\/10.suppl_2.43","article-title":"Interleukin-1 system crosstalk between embryo and endometrium in implantation","volume":"2","author":"Simon","year":"1995","journal-title":"Hum. Reprod."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chen, K., Liang, J., Qin, T., Zhang, Y., Chen, X., and Wang, Z. (2022). The Role of Extracellular Vesicles in Embryo Implantation. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.809596"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1242\/dev.124289","article-title":"Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome","volume":"142","author":"Vilella","year":"2015","journal-title":"Development"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Kusama, K., Suda, Y., Fujiwara, H., Hori, M., and Imakawa, K. (2020). Emerging Role of Extracellular Vesicles in Embryo-Maternal Communication throughout Implantation Processes. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155523"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1093\/humrep\/dead138","article-title":"Human blastocysts uptake extracellular vesicles secreted by endometrial cells containing miRNAs related to implantation","volume":"38","author":"Faus","year":"2023","journal-title":"Hum. Reprod."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2200107","DOI":"10.1002\/pmic.202200107","article-title":"Omics insights into extracellular vesicles in embryo implantation and their therapeutic utility","volume":"23","author":"Poh","year":"2023","journal-title":"Proteomics"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Teklenburg, G., Salker, M., Molokhia, M., Lavery, S., Trew, G., Aojanepong, T., Mardon, H.J., Lokugamake, A.U., Rai, R., and Landles, C. (2010). Natural selection of human embryos: Decidualizing endometrial stromal cells serve as sensors of embryo quality upon implantation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010258"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"dev201507","DOI":"10.1242\/dev.201507","article-title":"Human embryo implantation","volume":"150","author":"Muter","year":"2023","journal-title":"Development"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kovalevska, L., Shcherbak, S., and Kheifetz, I. (2024). The Role of the Endometrium in Implantation: A Modern View. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25179746"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"10077","DOI":"10.1038\/s41598-017-10098-3","article-title":"Meta-signature of human endometrial receptivity: A meta-analysis and validation study of transcriptomic biomarkers","volume":"7","author":"Koel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","first-page":"CD011872","article-title":"Metabolomics for improving pregnancy outcomes in women undergoing assisted reproductive technologies","volume":"3","author":"Siristatidis","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e-rbgo70","DOI":"10.61622\/rbgo\/2024rbgo70","article-title":"Immunosuppressants in women with repeated implantation failure in assisted reproductive techniques: A systematic review and meta-analysis","volume":"46","author":"Santos","year":"2024","journal-title":"Rev. Bras. Ginecol. Obstet."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"975","DOI":"10.1080\/14647273.2021.1955415","article-title":"Changes in the T-helper 1 and 2 cell populations during pregnancy in tacrolimus-treated women with repeated implantation failure and recurrent pregnancy loss","volume":"25","author":"Hisano","year":"2021","journal-title":"Hum. Fertil."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E13376","DOI":"10.1111\/aji.13376","article-title":"Analysis of the risk factors and treatment for repeated implantation failure: Optimization of Thyroid function, immunity, and Uterine Milieu (OPTIMUM) treatment strategy","volume":"85","author":"Kuroda","year":"2021","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.ejogrb.2019.06.007","article-title":"The effect of administration of intravenous intralipid on pregnancy outcomes in women with implantation failure after IVF\/ICSI with non-donor oocytes: A randomised controlled trial","volume":"240","author":"Singh","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Cheloufi, M., Kazhalawi, A., Pinton, A., Rahmati, M., Chevrier, L., Pratt-Ellenberg, L., Michel, A.S., Dray, G., Mekinian, A., and Kayem, G. (2021). The endometrial immune profiling may positively affect the management of recurrent preg nancy loss. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.656701"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1016\/j.ajog.2016.09.075","article-title":"Evidence that the endometrial microbiota has an effect on implantation success or failure","volume":"215","author":"Moreno","year":"2016","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"45","DOI":"10.5603\/GP.2020.0010","article-title":"Endometrial microbiota\u2014Do they mean more than we have expected?","volume":"91","author":"Mlodzik","year":"2020","journal-title":"Ginekol. Pol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4588\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T04:22:47Z","timestamp":1779510167000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4588"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":58,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104588"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104588","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}