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

Reframing Endometriosis: Interplay of NETs, Macrophages, and Lymphocytes at the Crossroads of Disease Progression, Infertility, and Malignant Transformation Megha M. Anchan Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India Search for more papers by this authorCorresponding Author Rahul Dutta Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India Center For Animal Research, Ethics & Training, Manipal Academy of Higher Education, Manipal, Karnataka, India Search for more papers by this authorMegha M. Anchan Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India Search for more papers by this authorCorresponding Author Rahul Dutta Division of Reproductive Biology, Department of Reproductive Science, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India Center For Animal Research, Ethics & Training, Manipal Academy of Higher Education, Manipal, Karnataka, India Search for more papers by this authorABSTRACT 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. Conflicts of Interest The authors declare no conflicts of interest. Data Availability Statement Data sharing is not applicable to this article, as no new data were created or analyzed in this study. References - 1S. Sourial, N. Tempest, and D. K. Hapangama, “Theories on the Pathogenesis of Endometriosis,” International Journal of Reproductive Medicine 2014 (2014): 179515. - 2L. Imperiale, M. Nisolle, J. C. Noël, and M. Fastrez, “Three Types of Endometriosis: Pathogenesis, Diagnosis and Treatment. State of the Art,” Journal of Clinical Medicine 12, no. 3 (2023): 994. - 3T. Bloski and R. 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