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Uterine natural killer (uNK) cells play a pivotal role in promoting placental development and supporting maternal-fetal immune tolerance, primarily through cytokine regulation and growth factor production. While the importance of uNK cells in pregnancy is well-established, the mechanisms of their interactions with trophoblasts and contributions to various pregnancy complications remain incompletely understood. This review highlights recent advancements in understanding uNK cell functions, with a focus on cytokine production, growth factor secretion, and receptor-ligand interactions, particularly involving killer immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C). We explore how uNK cell dysfunction contributes to pregnancy complications, including preeclampsia, recurrent pregnancy loss, and placenta accreta spectrum (PAS) disorders, emphasizing their roles in immune tolerance and placental health. By detailing the distinct cytokine signaling pathways and functional subtypes of uNK cells, this review provides insights into their regulatory mechanisms essential for pregnancy maintenance. Additionally, we discuss emerging therapeutic strategies targeting uNK-trophoblast interactions and propose future research directions, including the development of non-invasive biomarkers and personalized interventions. This comprehensive review addresses critical knowledge gaps, aiming to advance research in reproductive immunology and guide therapeutic innovations in maternal health. • uNK cell-derived cytokines and growth factors are vital for trophoblast invasion, artery remodeling, and immune tolerance. • Cytokine and growth factor profiles distinguish uNK cells from peripheral NK cells in placental support. • KIR-HLA-C interactions modulate uNK cytokine pathways to maintain maternal-fetal tolerance. • Aberrant uNK cytokine production is linked to preeclampsia, pregnancy loss, and PAS disorders. • Targeting uNK cytokine pathways offers new strategies for treating pregnancy complications.
Zhou et al. (Sat,) studied this question.