TREM2+ Macrophages Promote Immune Evasion in Endometriosis Through BAG3-Associated Regulation of CD8+ T Cell Autophagy

Macrophages are the most abundant immune cells in endometriotic lesions, but the roles of specific macrophage subsets in local immune dysfunction remain poorly understood. Here, combining single-cell RNA sequencing of 11 clinical samples with TREM2 knockout mouse models, co-culture experiments, and pharmacological intervention, we identify TREM2+ macrophages as an immunoregulatory population enriched in endometriosis. CD8+ T and natural killer (NK) cells in endometriotic lesions exhibited exhaustion-associated features and reduced cytotoxicity. Cell-cell communication analysis and functional experiments revealed that TREM2+ macrophages regulated CD8+ T cell activity through SPP1-CD44-associated communication and BAG3-associated autophagy regulation. In a mouse model of endometriosis, TREM2 deficiency enhanced CD8+ T and NK cell cytotoxicity and reduced ectopic lesion growth. Pharmacological disruption of the BAG3-HSP70 interaction with YM-1 impaired CD8+ T cell function and promoted lesion growth, and BAG3 silencing reduced autophagy-related markers and effector function in CD8+ T cells, supporting the involvement of BAG3-associated regulation in TREM2+ macrophage-mediated immune dysfunction. Our data identify TREM2+ macrophages as important regulators of immune dysregulation in endometriosis and highlight TREM2 as a potential target for future non-hormonal therapeutic strategies.