From Immune Dysregulation to Precision Immunotherapy in Recurrent Pregnancy Loss: A Narrative Review

Objective: Recurrent pregnancy loss (RPL) affects 1–5% of females of reproductive age, yet nearly half of these cases remain unexplained. This review synthesizes recent advances in understanding the immune-related causes of RPL and highlights how emerging technologies and precision medicine may help improve the diagnosis and treatment of RPL. Mechanism: Increasing evidence implicates immune dysregulation at the maternal–fetal interface as a cause of RPL, including aberrant uterine natural killer cell activation, Th17/Treg imbalance, impaired macrophage polarization, and disrupted cytokine signaling. These alterations compromise immune tolerance and increase the risk of miscarriage. Autoimmune disorders such as antiphospholipid syndrome and systemic lupus erythematosus, as well as alloimmune intolerance to paternal antigens, further contribute to pathogenic immune responses. Findings in Brief: Advances in single-cell RNA sequencing, spatial transcriptomics, and proteomic profiling have refined the understanding of decidual immune-cell states and identified candidate biomarkers—including human leukocyte antigen G (HLA-G), programmed death-ligand 1 (PD-L1), interleukin-10 (IL-10), and interleukin-17 (IL-17)—that distinguish tolerant from inflammatory microenvironments. Therapeutic approaches are shifting from the empirical use of glucocorticoids and anticoagulants toward mechanism-guided immunomodulation, incorporating calcineurin inhibitors, biologic agents, and emerging cellular therapies informed by immunophenotyping and molecular endotyping. Conclusions: Integrating immunology, multi-omics technologies, and artificial intelligence offers a pathway toward precision immunotherapy in RPL. This convergence supports the development of safer, personalized, and more effective diagnostic and therapeutic strategies for females with immune-mediated reproductive failure.