Deficient extravillous trophoblast invasion caused by impaired sialylation-Siglec-7 interaction contributes to recurrent pregnancy loss.

Successful pregnancy requires precise immune interactions between fetal extravillous trophoblasts (EVT) and maternal decidual immune cells at the maternal-fetal interface. Glycosylation, particularly terminal sialylation, is emerging as a key modulator of these interactions; however, its functional role in regulating the EVT-immune crosstalk remains poorly defined. Here, we aimed to identify a critical sialic acid-Siglec-7-IL-8-STAT3 signaling axis that promotes EVT invasiveness and is disrupted during recurrent pregnancy loss (RPL). Using primary human tissues and organ-on-chip models, we demonstrate that EVTs from patients with RPL exhibit reduced sialylation, coinciding with an increased proportion of Siglec-7⁺ decidual natural killer (dNK) cells. Mechanistically, sialylated glycoproteins on EVT surfaces engage Siglec-7, stimulating IL-8 secretion by dNK cells, which, in turn, activates STAT3 in EVTs to enhance migration and invasion. Restoration of EVT sialylation re-engages Siglec-7, rescues IL-8-STAT3 signaling, and restores invasive capacity. Our findings reveal that defective EVT sialylation disrupts a key immunological checkpoint that normally promotes EVT invasion and potentially contributes to RPL. This work provides direct mechanistic evidence that specific glycan-encoded immune signals at the maternal-fetal interface are critical for healthy pregnancy outcomes and suggests that modulating sialylation may offer a therapeutic strategy for RPL. Proposed model of sialic acid-Siglec-7-mediated regulation of EVT invasion through the ST6GALNAC6-sialic acid-Siglec-7-IL-8-STAT3 signaling axis. Schematic representation of the working model: enhanced sialylation of EVT membrane glycoproteins-driven by ST6GALNAC6-facilitates recognition by Siglec-7 expressed on dNK cells. This interaction promotes the activation of the IL-8-STAT3 signaling pathway, which supports EVT cell migration and invasion. Disruption of sialylation or Siglec-7 engagement impairs this pathway and reduces EVT invasiveness, potentially contributing to the pathogenesis of RPL. Figure created with BioRender.com ( https://BioRender.com/dxxt5az ).