{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T18:43:10Z","timestamp":1783536190128,"version":"3.55.0"},"reference-count":177,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"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>Oocyte formation occurs successfully within a meticulously controlled follicular environment characterized by well-documented endocrine, metabolic, and paracrine signals. Yet, the immunological landscape of the follicle and its role in influencing oocyte competency has received less attention in research. Growing research indicates that the ovarian follicle functions as an immunological-active niche necessitating a precise equilibrium between controlled inflammation and targeted immune tolerance. The programmed cell death-1 (PD-1) receptor and its ligand PD-L1 constitute a crucial immune checkpoint pathway, essential for sustaining peripheral immunological tolerance and averting excessive immune activation. Despite their comprehensive research in cancer biology and maternal\u2013fetal interactions, their possible function in the follicular microenvironment remains mostly unexamined. We propose that PD-1\/PD-L1 signaling may facilitate the formation of a localized immune-tolerant milieu inside the follicle to safeguard the developing oocyte from inflammatory injury and immune-mediated stress. The disturbance of this suggested equilibrium may lead to a pro-inflammatory follicular environment, compromised granulosa cell function, and modified oocyte maturation, hence affecting fertilization and embryonic developmental potential. In clinical contexts with immunological dysregulation, such as endometriosis, polycystic ovarian syndrome, and unexplained IVF failure, such processes may be especially significant. The purpose of this narrative review is to assimilate the current comprehension of immune regulation in the follicle with the established biology of PD-1\/PD-L1 and to investigate a potential correlation between immune checkpoint signaling, oocyte competence, and assisted reproductive outcomes. Considering the follicle as an immune-regulated microenvironment offers a new paradigm for comprehending infertility and identifying novel indicators or therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms27135712","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T05:48:16Z","timestamp":1782366496000},"page":"5712","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Follicular Immune Checkpoint: PD-1\/PD-L1 and Immune Tolerance in Oocyte Competence and IVF Failure"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9477-7619","authenticated-orcid":false,"given":"Charalampos","family":"Voros","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2990-640X","authenticated-orcid":false,"given":"Chrysi","family":"Christodoulaki","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, General Hospital of Chania, 73300 Chania, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Petrakou","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"},{"name":"MSc Program in High-Risk Pregnancy, School of Medicine, National and Kapodistrian University of Athens, 16673 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafaela","family":"Panagopoulou","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"},{"name":"MSc Program in High-Risk Pregnancy, School of Medicine, National and Kapodistrian University of Athens, 16673 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioanna","family":"Zouganeli","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"},{"name":"MSc Program in High-Risk Pregnancy, School of Medicine, National and Kapodistrian University of Athens, 16673 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3272-202X","authenticated-orcid":false,"given":"Dimos","family":"Sioutis","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fotios","family":"Chatzinikolaou","sequence":"additional","affiliation":[{"name":"Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Papadimas","sequence":"additional","affiliation":[{"name":"Athens Medical School, National and Kapodistrian University of Athens, 15772 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7108-211X","authenticated-orcid":false,"given":"Georgios","family":"Daskalakis","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, \u2018Alexandra\u2019 General Hospital, National and Kapodistrian University of Athens, 80 Vasilissis Sofias Avenue, 11528 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6565-1558","authenticated-orcid":false,"given":"Periklis","family":"Panagopoulos","sequence":"additional","affiliation":[{"name":"Third Department of Obstetrics and Gynecology, Attiko University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece"},{"name":"MSc Program in High-Risk Pregnancy, School of Medicine, National and Kapodistrian University of Athens, 16673 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1080\/19396368.2026.2631558","article-title":"Molecular mechanisms of folliculogenesis and oogenesis","volume":"72","author":"Ezz","year":"2026","journal-title":"Syst. 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