Reframing Endometriosis: Interplay of NETs, Macrophages, and Lymphocytes at the Crossroads of Disease Progression, Infertility, and Malignant Transformation

Endometriosis (ENDO) is a painful, chronic gynecological disease widely affecting women globally. While traditionally classified as a hormonal disorder, ENDO is now increasingly recognized as a multifaceted immune-mediated syndrome driven by chronic inflammation and immune tolerance. It is associated with painful symptoms, infertility, and potential malignant transformation. This study provides a comprehensive review of the immunological literature from electronic databases, focusing on the roles of innate and adaptive immune cell dysfunction in ENDO progression, including Neutrophil Extracellular Traps (NETs), macrophages, and lymphocytes. The pathology is governed by a dysregulated immunological landscape, specifically involving elevated NETs, the prevalence of immunosuppressive M2 macrophages, and compromised Natural Killer (NK) cell and T lymphocyte activity. These elements establish a tumor-like microenvironment through the activation of immune checkpoints and metabolic reprogramming. The chemokine IL-8 is highlighted as a central catalyst promoting NETosis and inflammation, driving fibrosis, lesion invasiveness, and reproductive failure. These immune circuits may also contribute to the risk of Endometriosis-Associated Ovarian Cancers. Reframing ENDO through this immunological paradigm provides an integrated model that incorporates its inflammatory, fibrotic, and carcinogenic features. This understanding reveals promising, non-hormonal therapeutic strategies targeting NETs, macrophage modulators, and immunological checkpoints for disease management and fertility preservation.