Recurrent pregnancy loss: Crosstalk between immune cells, decidual cells, and cellular autophagy

Recurrent pregnancy loss (RPL), affecting ∼5 % of couples, remains idiopathic in up to 50 % of cases. This review synthesizes the multifactorial pathogenesis of RPL, emphasizing dysregulated molecular pathways, genetic polymorphisms such as NOS2 rs2779249, and environmental triggers such as Toxoplasma gondii infection and pesticide exposure. Immune dysfunction is central, characterized by altered Treg subsets such as reduced CD4⁺ and increased CD8⁺ Tregs, impaired checkpoint expression such as PD-1/PD-L1 and Tim-3, aberrant cytokine profiles such as elevated IL-7, IL-1β, TNF-α and reduced TGF-β, and decidual NK (dNK) cell dysregulation impacting trophoblast invasion via pathways like IGF-2/PEG10. Non-coding RNAs further contribute by promoting trophoblast apoptosis, suppressing migration/invasion, and driving inflammation through MAPK/JNK/NF-κB signaling. Decidualization defects involve metabolic imbalance, unresolved endoplasmic reticulum stress, microRNA dysregulation, TNFα-induced senescence, and disrupted β-catenin/STAT3 crosstalk. Autophagy exhibits dual role: while protective in decidual stromal cells (DSCs) by supporting Treg expansion and immune tolerance, its dysregulation triggers trophoblast apoptosis via MCL-1 degradation and caspase activation. Environmental toxins exacerbate oxidative stress and apoptosis. Therapeutic prospects include immune checkpoint agonists, lncRNA/miRNA antagonists, autophagy flux modulators, growth factor therapies, and LMWH targeting thrombotic and inflammatory pathways. However, clinical translation faces challenges, including pathway duality, pleiotropic effects, targeted delivery limitations, and limited human trial data. Future research should focus on single-cell resolution studies, personalized approaches, and safer nanocarriers for biologics to bridge mechanistic insights into effective RPL interventions.