To systematically compare the phenotypic characteristics, functional heterogeneity, and clinical diagnostic value of peripheral blood natural killer (pNK) cells and uterine natural killer (uNK) cells in recurrent miscarriage (RM), and to analyze the current controversies and consensus regarding their role as diagnostic biomarkers.

This study is a narrative review of the literature. We comprehensively analyzed published research on the immunological mechanisms of RM, with a focus on the comparative biology of pNK and uNK cells. The analysis encompassed studies on surface marker profiles, transcriptional regulation, functional heterogeneity (cytotoxicity, cytokine secretion, and trophoblast interaction), clinical detection techniques, diagnostic value, and evidence from immunotherapy trials.

pNK and uNK cells exhibit significant phenotypic and functional heterogeneity. pNK cells are predominantly CD56dimCD16+ with high cytotoxicity, while uNK cells are mainly CD56brightCD16−, playing a dual role in immune tolerance and vascular remodeling. In RM patients, pNK cell proportions and cytotoxic activity are frequently elevated, with some studies suggesting predictive thresholds (e.g., ≥33% cytotoxicity, OR=3.4), but a lack of standardized cut-off values and inconsistent correlations with pregnancy outcomes limit its clinical utility. Conversely, uNK cell density in the endometrium is often increased in idiopathic RM (e.g., 257±212 vs. 148±73 cells/mm²), but paradoxically, their degranulation activity and expression of key receptors (e.g., KIR2DL1/S1, LILRB1) may be reduced, indicating functional impairment. The clinical application of uNK cell assessment is further hindered by the invasiveness of endometrial biopsy, stringent timing requirements, and significant biological variability. There is no established correlation between pNK and uNK levels. Current detection technologies, including flow cytometry and cytotoxicity assays, face challenges in standardization and reproducibility across centers. Immunotherapies targeting NK cells, such as intravenous immunoglobulin (IVIG), have shown potential in modulating pNK levels but lack robust evidence for improving live birth rates, with guidelines not recommending their routine use.

Both pNK and uNK cells are involved in the pathogenesis of RM, but neither serves as a reliable standalone diagnostic biomarker due to inconsistent clinical cut-offs, substantial biological and methodological heterogeneity, and a poor correlation with each other. The roles of NK cells are highly context-dependent, determined not just by cell number but by functional status, tissue microenvironment, and intricate cellular interactions. Future research should prioritize the use of single-cell multi-omics to identify disease-specific functional subsets, establish standardized protocols for NK cell assessment, and develop integrated multi-omics predictive models to enable precise immunological stratification and guide individualized therapeutic strategies for patients with RM.