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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

The Role of Immunologic Factors in Endometrial Receptivity: An Embryo–Endometrium Dialogue

by
Evangelia Panagodimou
1,
Ianthi Terzopoulou
2,
Olga Triantafyllidou
3,
Georgios Markantes
2,
Neoklis Georgopoulos
2,
Nikolaos Vlahos
3,
George Adonakis
2 and
Apostolos Kaponis
2,*
1
Department of Obstetrics & Gynecology, IASO Clinic, 151 23 Athens, Greece
2
Department of Obstetrics & Gynecology, Medical School, University of Patras, 262 21 Patron, Greece
3
Department of Obstetrics & Gynecology, Aretaieio Hospital, Medical School of Athens, 115 28 Athens, Greece
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(10), 4588; https://doi.org/10.3390/ijms27104588
Submission received: 16 March 2026 / Revised: 26 April 2026 / Accepted: 18 May 2026 / Published: 20 May 2026
(This article belongs to the Special Issue Molecular Pathways to Infertility)
Review Reports Versions Notes

Abstract

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—including JAK/STAT, PI3K/AKT, NF-κB, and MAPK—that integrate immune and decidual responses. The bidirectional embryo–endometrium 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.
Keywords: endometrial receptivity; embryo implantation; uterine natural killer cells; regulatory T cells; embryo–endometrium communication; reproductive immunology; cytokines; signaling pathways; recurrent implantation failure endometrial receptivity; embryo implantation; uterine natural killer cells; regulatory T cells; embryo–endometrium communication; reproductive immunology; cytokines; signaling pathways; recurrent implantation failure

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MDPI and ACS Style

Panagodimou, E.; Terzopoulou, I.; Triantafyllidou, O.; Markantes, G.; Georgopoulos, N.; Vlahos, N.; Adonakis, G.; Kaponis, A. The Role of Immunologic Factors in Endometrial Receptivity: An Embryo–Endometrium Dialogue. Int. J. Mol. Sci. 2026, 27, 4588. https://doi.org/10.3390/ijms27104588

AMA Style

Panagodimou E, Terzopoulou I, Triantafyllidou O, Markantes G, Georgopoulos N, Vlahos N, Adonakis G, Kaponis A. The Role of Immunologic Factors in Endometrial Receptivity: An Embryo–Endometrium Dialogue. International Journal of Molecular Sciences. 2026; 27(10):4588. https://doi.org/10.3390/ijms27104588

Chicago/Turabian Style

Panagodimou, Evangelia, Ianthi Terzopoulou, Olga Triantafyllidou, Georgios Markantes, Neoklis Georgopoulos, Nikolaos Vlahos, George Adonakis, and Apostolos Kaponis. 2026. "The Role of Immunologic Factors in Endometrial Receptivity: An Embryo–Endometrium Dialogue" International Journal of Molecular Sciences 27, no. 10: 4588. https://doi.org/10.3390/ijms27104588

APA Style

Panagodimou, E., Terzopoulou, I., Triantafyllidou, O., Markantes, G., Georgopoulos, N., Vlahos, N., Adonakis, G., & Kaponis, A. (2026). The Role of Immunologic Factors in Endometrial Receptivity: An Embryo–Endometrium Dialogue. International Journal of Molecular Sciences, 27(10), 4588. https://doi.org/10.3390/ijms27104588

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