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Recurrent pregnancy loss (RPL), particularly its unexplained form (URPL), represents a formidable challenge in reproductive medicine. Although traditionally attributed to local immune imbalances at the maternal-fetal interface, this perspective may not fully account for the condition’s upstream etiological drivers and recurrent nature. This review transcends this limitation by proposing and systematically substantiating an integrative ‘gut-systemic-decidual’ model of immunometabolic dysregulation. We posit that a key pathological cascade in many URPL cases may originate with distal gut dysbiosis, which, through imbalanced metabolite profiles and the leakage of inflammatory molecules such as lipopolysaccharide (LPS), triggers systemic ‘metabolic endotoxemia’ and fundamentally reprograms the metabolic state of circulating immune cells. This systemic ‘first hit’ is compounded when these ‘pre-sensitized’ cells migrate to an equally metabolically stressed and ‘hostile’ decidual microenvironment—a ‘second hit’ characterized by hypoxia and high lactate. This culminates in the functional collapse of the core sentinels of maternal-fetal tolerance, namely regulatory T (Treg) and decidual natural killer (dNK) cells, due to profound metabolic misprogramming. Ultimately, this integrated model elevates the etiological understanding of URPL from a ‘local conflict’ to that of a ‘systemic disease,’ paving the way for the development of dynamic warning systems that integrate multi-omics data and for the design of multi-level precision intervention strategies targeting patient stratification and preventive approaches for the gut, systemic metabolism, and the local microenvironment.

Placenta-specific trophoblast and tumor cells exhibit many common characteristics. Trophoblast cells invade maternal tissues while being tolerated by the maternal immune system. Similarly, tumor cells can invade surrounding tissues and escape the immune system. Importantly, both trophoblast and tumor cells are supported by an abetting microenvironment, which influences invasion, angiogenesis, and immune tolerance/evasion, among others. However, in contrast to tumor cells, the metabolic, proliferative, migrative, and invasive states of trophoblast cells are under tight regulatory control. In this review, we provide an overview of similarities and dissimilarities in regulatory processes that drive trophoblast and tumor cell fate, particularly focusing on the role of the abetting microenvironments.

Background Recurrent miscarriage (RM) remains a significant clinical challenge due to insufficient understanding of decidual microenvironment dysfunction and limited effective therapeutic options. Current treatments primarily focus on immunomodulation and hormonal therapy, which often fail to address the underlying decidual communication defects. This study investigates growth arrest-specific gene 1 (GAS1) as a potential therapeutic target for RM by elucidating its role in extracellular vesicle (EV)-mediated decidual communication and developing a novel RNA nanotechnology-based delivery system for targeted uterine treatment. Results GAS1 is identified as a critical regulator of the biogenesis of EVs in decidual stromal cells (DSCs), and its deficiency is strongly associated with pregnancy-related pathologies. Mechanistic investigations suggest that GAS1 modulates RAB39B, a key regulator involved in EV biogenesis and transport, potentially contributing to decidual homeostasis. EVs derived from GAS1-overexpressing DSCs (GAS1-EVs) are enriched in GAS1 protein, forming a self-reinforcing loop for decidual support, while their reprogrammed cargo facilitates embryonic adhesion, trophoblast migration, and angiogenesis. The use of Atosiban-conjugated three-way junction-pRNA (3WJ-pRNA) for the targeted delivery of GAS1-enhanced EVs (Atosiban-GAS1-EVs) to the uterus in early pregnancy is explored, offering a promising non-invasive targeted treatment for women with RM. This targeted approach restores decidual microenvironment organization and reduces fetal resorption rates in murine RM models. Conclusions This study unveils that the GAS1-RAB39B axis may play a significant role in EV-mediated decidual communication and provide a potential non-invasive, RNA nanotechnology-driven strategy for RM treatment. Graphical Abstract

Obstetric antiphospholipid syndrome (OAPS) is an autoimmune disorder characterized by pathologic pregnancies and the presence of antiphospholipid antibodies (aPLs). Despite significant infiltration of decidual macrophages observed in OAPS patients, the underlying connections between decidual and peripheral immune cells remain unclear. In this study, an integrated single‐cell atlas is constructed of the decidua and peripheral blood mononuclear cells (PBMCs) from OAPS patients and HCs. Using this atlas, substantial disparities are identified in immune cells between the decidua and PBMCs. The functional changes in immune cells of OAPS patients are also different in decidua and PBMCs. Moreover, increased infiltration of monocyte‐derived macrophages (MDMs) into the decidua is found to contribute to inflammation and trophoblast dysfunction in OAPS. The role of CCL2 is further discovered in recruiting MDMs, driven by excess CCL2 secreted from decidual macrophages stimulated by the aPLs and β2‐glycoprotein I complex via the TLR4‐NF‐κB pathway. Decidual vascular endothelial cells express higher levels of ACKR1, which aggregates CCL2 on their surface. Targeting CCR2 and TLR4 improved pregnancy outcomes in OAPS mouse models induced by aPLs, suggesting that these pathways may serve as potential therapeutic targets for OAPS. This study provides new insights into the pathogenesis of OAPS, particularly regarding decidual MDMs infiltration. This study uncovers a novel mechanism and therapeutic targets in obstetric antiphospholipid syndrome (OAPS). Antiphospholipid antibody/ß2‐glycoprotein I complex boosts CCL2 and TNF‐α expression in decidual macrophages via TLR4‐NF‐κB. CCL2 accumulates on endothelial surfaces via ACKR1, recruiting monocyte‐derived CCR2+ macrophages, driving inflammation, and impairing trophoblast function. Targeting TLR4 and CCR2 may benefit OAPS treatment.

Recurrent pregnancy loss (RPL) is a heterogeneous reproductive disorder in which dysregulation of maternal–fetal 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–metabolic signatures associated with impaired trophoblast function and vascular remodeling, while emerging microbiome studies suggest a gut–reproductive 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.

The success of pregnancy relies on the fine adjustment of the maternal immune system to tolerate the allogeneic fetus. Trophoblasts carrying paternal antigens are the only fetal-derived cells that come into direct contact with the maternal immune cells at the maternal–fetal interface. The crosstalk between trophoblasts and decidual immune cells (DICs) via cell–cell direct interaction and soluble factors such as chemokines and cytokines is a core event contributing to the unique immunotolerant microenvironment. Abnormal trophoblasts–DICs crosstalk can lead to dysregulated immune situations, which is well known to be a potential cause of a series of pregnancy complications including recurrent spontaneous abortion (RSA), which is the most common one. Immunotherapy has been applied to RSA. However, its development has been far less rapid or mature than that of cancer immunotherapy. Elucidating the mechanism of maternal–fetal immune tolerance, the theoretical basis for RSA immunotherapy, not only helps to understand the establishment and maintenance of normal pregnancy but also provides new therapeutic strategies and promotes the progress of immunotherapy against pregnancy-related diseases caused by disrupted immunotolerance. In this review, we focus on recent progress in the maternal–fetal immune tolerance mediated by trophoblasts–DICs crosstalk and clinical application of immunotherapy in RSA. Advancement in this area will further accelerate the basic research and clinical transformation of reproductive immunity and tumor immunity.

Lactic acid (LA) metabolism in the tumor microenvironment contributes to the establishment and maintenance of immune tolerance. This pathway is characterized in tumor associated macrophages. However, the role and pathway of LA metabolism at maternal-fetal interface during early pregnancy, especially in decidual macrophage differentiation, are still unclear. Herein, for the first time, we discovered that LA can trigger either M2 or M1 macrophage polarization via oxidative phosphorylation and glycolysis regulation under normoxia or hypoxia, respectively. Also, LA metabolism played a vital role in decidual macrophages-mediated recurrent pregnancy loss (RPL), through HIF-1α/SRC/LDHA pathway. Moreover, blockade of LA intake with AZD3965 (MCT-1 inhibitor) could rescue pregnancy in an abortion-prone mouse model, suggesting a potential therapeutic target in RPL. Collectively, the present study identifies the previously unknown functions of LA metabolism in the differentiation of decidual macrophages in early normal pregnancy and RPL, and provides a potential therapeutic strategy in RPL by manipulating decidual macrophages' functions through LA metabolic pathway.

Natural killer (NK) cells are crucial to various facets of human immunity and function through direct cytotoxicity or via orchestration of the broader immune response. NK cells exist across a wide range of functional and phenotypic identities. Murine and human studies have revealed that NK cells possess substantial plasticity and can alter their function and phenotype in response to external signals. NK cells also play a critical role in tumor immunity and form the basis for many emerging immunotherapeutic approaches. NK cells can directly target and lyse malignant cells with their inherent cytotoxic capabilities. In addition to direct targeting of malignant cells, certain subsets of NK cells can mediate antibody-dependent cellular cytotoxicity (ADCC) which is integral to some forms of immune checkpoint-blockade immunotherapy. Another important feature of various NK cell subsets is to co-ordinate anti-tumor immune responses by recruiting adaptive and innate leukocytes. However, given the diverse range of NK cell identities it is unsurprising that both pro-tumoral and anti-tumoral NK cell subsets have been described. Here, NK cell subsets have been shown to promote angiogenesis, drive inflammation and immune evasion in the tumor microenvironment. To date, the signals that drive tumor-infiltrating NK cells towards the acquisition of a pro- or anti-tumoral function are poorly understood. The notion of tumor microenvironment-driven NK cell plasticity has substantial implications for the development of NK-based immunotherapeutics. This review will highlight the current knowledge of NK cell plasticity pertaining to the tumor microenvironment. Additionally, this review will pose critical and relevant questions that need to be addressed by the field in coming years.

Decidual protein induced by progesterone (DEPP1) was identified to exert heterogeneous functions in several cancers, whereas its role in gastric cancer (GC) remains elusive. In the present study, differential expression analysis was conducted using three Gene Expression Omnibus datasets (GSE54129, GSE26942 and GSE3438). Validation of DEPP1 expression was performed using reverse transcription-quantitative PCR, western blotting and immunofluorescence. Kaplan-Meier survival and Cox regression analyses were employed to assess the association between DEPP1 expression and the prognosis of patients with GC. Immune infiltration analysis was conducted to explore the correlation between DEPP1 and the tumor microenvironment. The potential of DEPP1 to promote oxaliplatin resistance was assessed using flow cytometry, western blotting, and subcutaneous mouse models. DEPP1 was found to be significantly upregulated in the aforementioned cohorts, which was consistent with the clinical specimens of the present study, and it emerged as an independent risk factor for poor overall survival in patients with GC. A prognostic nomogram was developed to improve prognosis prediction. High DEPP1 expression correlated with increased infiltration of cancer-associated fibroblasts, endothelial cells, and M2 macrophages, contributing to the development of a stroma-rich and immunosuppressive microenvironment in GC. Furthermore, high DEPP1 expression was associated with reduced sensitivity to chemotherapy drugs in patients with GC. In vitro and in vivo experiments highlighted DEPP1′s crucial role in promoting oxaliplatin resistance in GC. In conclusion, DEPP1 is identified as a promising prognostic biomarker linked to a stroma-rich and immunosuppressive microenvironment, and it is critical in driving oxaliplatin resistance in GC. These findings may inform personalized therapeutic strategies for patients with GC.

The pregnant uterus is an immunologically rich organ, with dynamic changes in the inflammatory milieu and immune cell function underlying key stages of pregnancy. Recent studies have implicated dysregulated expression of the interleukin-1 (IL-1) family cytokine, IL-33, and its receptor, ST2, in poor pregnancy outcomes in women, including recurrent pregnancy loss, preeclampsia, and preterm labor. How IL-33 supports pregnancy progression in vivo is not well understood. Here, we demonstrate that maternal IL-33 signaling critically regulates uterine tissue remodeling and immune cell function during early pregnancy in mice. IL-33–deficient dams exhibit defects in implantation chamber formation and decidualization, and abnormal vascular remodeling during early pregnancy. These defects coincide with delays in early embryogenesis, increased resorptions, and impaired fetal and placental growth by late pregnancy. At a cellular level, myometrial fibroblasts, and decidual endothelial and stromal cells, are the main IL-33⁺ cell types in the uterus during decidualization and early placentation, whereas ST2 is expressed by uterine immune populations associated with type 2 immune responses, including ILC2s, Tregs, CD4⁺ T cells, M2- and cDC2-like myeloid cells, and mast cells. Early pregnancy defects in IL-33–deficient dams are associated with impaired type 2 cytokine responses by uterine lymphocytes and fewer Arginase-1⁺ macrophages in the uterine microenvironment. Collectively, our data highlight a regulatory network, involving crosstalk between IL-33–producing nonimmune cells and ST2⁺ immune cells at the maternal–fetal interface, that critically supports pregnancy progression in mice. This work has the potential to advance our understanding of how IL-33 signaling may support optimal pregnancy outcomes in women.