BackgroundEndometriosis (EMs) is a chronic inflammatory condition that is highly heterogeneous. Current clinical staging fails to accurately predict drug responses and prognosis. In this study, we aimed to reveal the heterogeneity of ectopic lesions and investigate the possible underlying mechanisms using transcriptomic data and clinical information.MethodsThe EMs microarray dataset GSE141549 was obtained from the Gene Expression Omnibus database. Unsupervised hierarchical clustering was performed to identify EMs subtypes, which was followed by the functional enrichment analysis and estimation of immune infiltrates. Subtype-associated gene signatures were identified and further validated in other independent datasets, including GSE25628, E-MTAB-694, and GSE23339. Additionally, tissue microarrays (TMAs) were generated from premenopausal patients with EMs to investigate the potential clinical implications of the two identified subtypes.ResultsThe unsupervised clustering analysis revealed that ectopic EMs lesions can be classified into two distinct subtypes: stroma-enriched (S1) and immune-enriched (S2). The functional analysis revealed that S1 correlated with fibroblast activation and extracellular matrix remodeling in the ectopic milieu, whereas S2 was characterized by the upregulation of immune pathways and a higher positive correlation with the immunotherapy response. Moreover, we identified a subtype signature composed of FHL1 and SORBS1, and constructed a subtype diagnostic model. Based on the cohort data from the TMAs, we found that S2 was strongly associated with the failure of/intolerance to hormone therapy.ConclusionsThis study identified two distinct subtypes that are varyingly associated with hormone resistance, stroma-immunity, and molecular features, thereby highlighting the importance of this stromal-immune heterogeneity in identifying EMs subtypes and providing novel insights into future personalized hormone-free therapy in EMs.