Single-cell transcriptome reveals that immune cells inhibit the repairment of IGFBP3 + stromal cells in thin endometrium

Thin endometrium (TE), affecting 1.5 %–9.1 % of reproductive-aged women, emerges as a disturbed decidua microenvironment underpinning implantation failure and recurrent pregnancy loss. Through integrated single-cell transcriptomics with histopathology and multiplex immunofluorescence (TSA) validation, we delineated TE as a disease of coordinated repairment impairment and pro-fibrotic remodeling across stromal and immune compartments. Key findings revealed a pathological imbalance in stromal subsets, including the decrease of regenerative IGFBP3 + Stromal_1 cells and expansion of fibrogenic Stromal_2 populations, driving collagen-dominant extracellular matrix remodeling. Concurrently, immune dysfunction was unmasked. NK cells decreased and shifted from immune surveillance to a pro-inflammatory phenotype, T cells transitioned from immune regulation to extracellular matrix remodeling effectors and macrophages adopted a pro-fibrotic phenotype with lipid metabolic collapse. CellChat analysis pinpointed suppression of GZMA-PARD3 and APOE-TREM2 axes as drivers of stromal dysfunction, while the hyperactivated adhesion (LAMA3) and collagen pathways served as central mediators of the fibro-inflammatory cascade. These findings, based on single-cell RNA-seq and spatial verification, suggest therapeutic targets for restoring endometrial homeostasis in TE. These findings suggested that TE as a disease of progressive stromal-immune fibrosis dysregulation, offering novel therapeutic targets to restore endometrial repairment and microenvironmental homeostasis. • Single-cell atlas reveals coordinated stromal-immune fibrotic remodeling in thin endometrium. • Single-cell sequencing analysis suggests functional reprogramming of NK/T cells from immune surveillance to collagenogenic-angiogenic effectors drives disease progression. • Single-cell RNA-seq reveals macrophage-stromal APOE-TREM2 axis disruption links lipid metabolic dysregulation to immune dysfunction. • Single-cell transcriptomic profiling indictates LAMA3/COL1A1 axis hyperactivation establishes collagen-dominant extracellular matrix niche in thin endometrium. • GZMA-PARD3 signaling suppression was found by impairs immune-stromal crosstalk in endometrial regeneration by single-cell sequencing analysis.