This review centers on the maternal–fetal interface and focuses on the role of macrophages throughout the course of pregnancy. First, pregnancy is presented as a finely balanced immunological process: the mother must maintain tolerance toward the fetus, which carries paternal antigens, while preserving sufficient immune defenses against infection. The maternal-fetal interface is composed of decidua, placental trophoblasts, and multiple immune cell populations. Among them, decidual macrophages are present in substantial numbers and are key cells in maintaining local immune homeostasis and mediating tissue remodeling. Across early, mid, and late pregnancy, these cells exhibit marked temporal and functional heterogeneity: they are skewed toward a pro-inflammatory phenotype in early pregnancy to facilitate implantation and invasion, toward a tolerogenic and reparative phenotype in mid-gestation, and then again toward a pro-inflammatory state near term to help initiate labor.
On this basis, the review systematically outlines the multilayered regulatory networks that drive M1/M2 polarization of macrophages. At the level of immune regulation, pathways such as the Tregs/IL-10/TGF-β axis, Th2-type cytokines, and M-CSF collectively promote the establishment and maintenance of the M2 phenotype. In terms of innate immunity, pattern-recognition receptors such as TLR4 promote M1 polarization and amplify inflammation through NF-κB and MAPK signaling cascades. Metabolically, enhanced glycolysis, accumulation of succinate and ROS, and stabilization of HIF-1α in turn shape macrophage functional states. In addition, multiple miRNAs, lncRNAs, and circRNAs participate in fine-tuning macrophage polarization by targeting key signaling molecules or functioning as competing endogenous RNAs. Together, these factors determine the dynamic balance between pro-inflammatory and tolerogenic macrophage states at the maternal–fetal interface.
The review further points out that once macrophage polarization becomes imbalanced, or when their capacity to clear apoptotic cells is impaired, a range of adverse pregnancy outcomes can ensue. In recurrent miscarriage, an increased proportion of M1 macrophages, reduced M2 cells, and Th17/Treg imbalance are frequently observed, suggesting that excessive inflammation and breakdown of immune tolerance contribute to embryonic loss. Placental insufficiency and fetal growth restriction are closely associated with M1-skewed macrophage polarization and impaired angiogenesis in the placenta and decidua. In the context of preterm birth and intrauterine infection, strong TLR4-mediated inflammatory responses can trigger massive release of pro-inflammatory cytokines, enhance uterine contractions, and promote cervical ripening, thereby precipitating premature onset of labor. Collectively, these observations support the view that macrophages function as a crucial hub linking immune dysregulation to pregnancy complications.
Finally, the review discusses potential therapeutic targets and remaining challenges. On the one hand, targeting pathways such as PPAR-γ, IL-10, and the MerTK/MFG-E8 axis, or using non-coding RNAs such as miRNAs and lncRNAs to modulate macrophage polarization, is considered a promising strategy to restore immune homeostasis at the maternal-fetal interface and improve outcomes in miscarriage, placenta-related disorders, and preterm birth. On the other hand, how to achieve tissue-specific and temporally precise drug delivery, and how to ensure the safety of both mother and fetus, remain key issues for future clinical and translational studies. Overall, this work provides a relatively comprehensive framework for understanding the cellular basis of maternal-fetal immune balance and for developing macrophage-targeted therapies in pregnancy.
Literature review
Not applicable
Dynamics and Regulation of Maternal–Fetal Interface Macrophages: From Immune Tolerance to Pregnancy Outcomes
6-Dec-2025
The authors declare no conflicts of interest.