Decoding interferon-mediated spatiotemporal regulation at the maternal-fetal interface.

Abstract

Successful pregnancy requires precise regulation of the maternal-fetal immune microenvironment, where maternal immune tolerance toward the semi-allogeneic fetus must be balanced with effective antimicrobial defense. Interferons (IFNs), a family of pleiotropic immunoregulatory cytokines, are central to this process. Produced by endometrial cells, decidual stromal cells, trophoblasts, and decidual immune cells, IFNs establish a highly coordinated signaling network that regulates endometrial receptivity, decidualization, trophoblast differentiation and invasion, spiral artery remodeling, and immune homeostasis. Unlike canonical systemic interferon responses, IFN activity at the maternal-fetal interface is precisely controlled in a cell type-, spatial-, and temporal-specific manner, thereby limiting excessive inflammation while preserving host defense. Disruption of this tightly regulated network is increasingly recognized as a key driver of pregnancy complications, including preeclampsia (PE), recurrent pregnancy loss (RPL), recurrent implantation failure (RIF), preterm birth, and fetal growth restriction. In this Review, we summarize the cellular sources, spatiotemporal regulation, molecular mechanisms, and physiological functions of IFNs at the maternal-fetal interface, and discuss how aberrant IFN signaling contributes to adverse pregnancy outcomes. We further highlight emerging opportunities for biomarker development and targeted immunomodulatory therapies, providing a conceptual framework for translating mechanistic insights into precision reproductive medicine.