The immunological paradox of tubal ectopic pregnancy: unraveling immune tolerance amidst inflammation via single-cell sequencing

Tubal ectopic pregnancy (TEP) is a common and serious obstetric complication with unclear pathogenesis. This study aims to use single-cell RNA sequencing (scRNA-seq) to analyze immune cell composition and functional changes in implantation sites (IS) and non-implantation sites (NIS) of fallopian tube tissues from TEP patients, exploring potential pathogenesis. We performed scRNA-seq on IS and NIS tubal tissues from TEP patients, constructing a high-resolution immune atlas. Differential expression and functional enrichment analysis were applied to reveal functional reprogramming in key immune subsets. We identified a total of 28 cell clusters encompassing 13 major cell types, and T/NK cells and macrophages as the predominant populations. Further subcluster analysis demonstrated CD4⁺ memory T cells (CD4⁺ Tm) enriched at the IS exhibited both pro-inflammatory and immune-tolerant function; CD8⁺ KLRC2⁺ effector T cells and CD8⁺ memory T cells (CD8⁺ Tm) were reduced in proportion and functionally impaired; monocyte numbers increased, contributing to chronic inflammation and abnormal angiogenesis; M1 macrophages decreased while M2 macrophages increased, promoting immune tolerance, angiogenesis, and extracellular matrix remodeling. Therefore, functional reprogramming and altered cellular composition of the TEP immune microenvironment underlie both transient ectopic embryo survival and tubal tissue damage. This study reveals the key roles of CD4⁺ Tm cells, CD8⁺ KLRC2⁺ Teff cells, CD8⁺ Tm cells, monocytes, and M1/M2 macrophages, offering insights into the pathogenesis of TEP and potential immunological interventions.