What question did this study set out to answer?

The research aims to investigate the specific immune microenvironments and signaling pathways in peritoneal versus ovarian endometriosis.

April 22, 2026Open Access

Integrated single-cell and spatial transcriptomics reveal divergent immunological and stromal programs in peritoneal versus ovarian endometriosis

Key Points

The research aims to investigate the specific immune microenvironments and signaling pathways in peritoneal versus ovarian endometriosis.
Integrated analysis of single-cell RNA sequencing and spatial transcriptomic data
Construction of cellular atlases and cell-cell communication networks
Differential expression analysis to identify subtype-specific pathways.
Distinct cellular ecosystems were found in peritoneal endometriosis with increased CCL19 + perivascular cells and immune activity.
Ovarian endometriosis showed enhanced smooth muscle differentiation with significant gene upregulation of MYH11.
Divergent signaling pathways were identified, highlighting immune-mediated mechanisms in peritoneal endometriosis and fibromuscular pathways in ovarian endometriosis.

Abstract

Endometriosis encompasses heterogeneous lesions, primarily peritoneal and ovarian subtypes, with distinct immunological and fibrotic features. The subtype-specific roles of the immune microenvironment in pathogenesis remain unclear. Integrated analysis combining high-resolution cellular atlases with spatial context is needed to decipher these mechanisms. We performed an integrative analysis of published single-cell RNA sequencing (n = 81,676 cells) from control endometrium (Ctrl), eutopic endometrium (EuE), peritoneal endometriosis (EcP), and ovarian endometriosis (EcO), and spatial transcriptomic (n = 60 segments) data from Ecp and match EuE. Analytical pipelines include cellular atlas construction, differential expression, spatial co-expression, and cell-cell communication inference. Our single-cell atlas revealed fundamentally distinct cellular ecosystems. EcP was enriched for CCL19 + perivascular cells (6.4-fold vs. control) and immune-active niches, whereas EcO exhibited pronounced smooth muscle differentiation and NNMT upregulation. Spatial analysis compartmentalized these programs, with the CCL19-CCR7 chemokine axis localized to stromal niches in EcP strongly correlated (ρ = 0.872). In contrast, EcO showed enhanced smooth muscle gene expression (MYH11, log₂FC = 3.87). Cell-cell communication networks diverged, with EcP dominated by chemokine and TGF-β signaling, and EcO dominated by smooth muscle and PDGF pathways. Therapeutic target analysis revealed subtype-specific patterns: immune checkpoints (CTLA4 and PDCD1) were upregulated in EcP, whereas MMP9 was dramatically downregulated in EcO. EcP and EcO exhibit fundamentally divergent programs. We propose to conceptualize these as an ‘immune-hot’, chemokine-driven inflammatory niche (EcP) versus an ‘immune-cold’, fibromuscular survival niche (EcO). These findings underscore that lesion-specific immune-stromal crosstalk may dictates pathogenesis and suggest a potential paradigm shift toward immunologically-informed, subtype-specific precision therapeutics, which warrant further experimental validation.

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