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Immunol."],"abstract":"<jats:p>Recurrent pregnancy loss (RPL) is a heterogeneous reproductive disorder in which dysregulation of maternal\u2013fetal immune tolerance, aberrant decidual immune remodeling, and altered inflammasome signaling have been implicated within a complex multi-omics landscape. Multi-omics profiling (genomics, epigenomics, single-cell\/spatial transcriptomics, proteomics, metabolomics, microbiome analyses, and immunomics) is increasingly being used to characterize mechanistic heterogeneity in RPL and to support biomarker discovery and immune-informed stratification. Genomic studies have associated chromosomal abnormalities and pathogenic variants with early embryonic developmental failure, while epigenomic profiling has highlighted aberrant methylation patterns and imprinting disturbances. Single-cell and spatial transcriptomics have revealed altered cellular composition and disrupted communication among decidual stromal cells, uterine natural killer (uNK) cells, macrophages, regulatory T cells (Treg), T helper 17 (Th17) cells, and trophoblast lineages. Proteomic and metabolomic studies have further identified immune\u2013metabolic signatures associated with impaired trophoblast function and vascular remodeling, while emerging microbiome studies suggest a gut\u2013reproductive axis that may modulate systemic immune homeostasis. Integration of multi-omics datasets with computational frameworks (e.g., weighted gene co-expression network analysis (WGCNA), multi-omics factor analysis (MOFA), and deep-learning models may improve RPL subtype classification, risk prediction, and the identification of potentially actionable pathways. However, current studies remain limited by small cohort sizes, especially in single-cell datasets, cross-platform heterogeneity, insufficient longitudinal validation, and a lack of multicenter reproducibility. Future work should prioritize standardized multi-omics pipelines, clearer evidence stratification, and immune-centric analytical frameworks to improve the robustness and translational relevance of RPL research. These advances may ultimately support immune-informed risk assessment and contribute to the gradual development of more individualized management strategies for RPL.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1811970","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:45:20Z","timestamp":1777437920000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Multi-omics insights into immune tolerance at the maternal\u2013fetal interface in recurrent pregnancy loss: mechanisms, integration challenges, and translational perspectives"],"prefix":"10.3389","volume":"17","author":[{"given":"Mengqiu","family":"Shao","sequence":"first","affiliation":[{"name":"Yunnan University of Chinese Medicine","place":["Kunming, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yunnan University of Chinese 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