Macrophage Polarization and Metabolic Reprogramming in Endometriosis: Mechanisms and Therapeutic Implications

Abstract

This review synthesizes evidence on macrophage roles, polarization (M1/M2), and immunometabolic/signaling pathways in endometriosis, outlining therapeutic implications. We searched PubMed, Cochrane Library, ClinicalTrials.gov, Scopus, Embase, and Google Scholar. Available evidence demonstrates increased macrophage accumulation and substantial heterogeneity across the eutopic endometrium, peritoneal fluid, and established endometriotic lesions. Rather than undergoing a uniform shift from an M1 to an M2 phenotype, endometriosis-associated macrophages acquire overlapping inflammatory, immunoregulatory, angiogenic, phagocytic, metabolic, and profibrotic programs. Endometriotic epithelial and stromal cells regulate macrophage recruitment and activation through estrogen receptor β–NF-κB–CCL2 signaling, IL-17A- and TNF-α-dependent cytokine production, extracellular-vesicle-mediated microRNA transfer, and lactate-driven METTL3–Trib1–ERK/STAT3 signaling. The CCL2/MCP-1–CCR2 axis further links monocyte recruitment with inflammatory signaling and the invasive behavior of endometriotic cells, whereas TET3-mediated suppression of let-7 microRNAs sustains disease-associated macrophage activation. Functionally, macrophages contribute to defective clearance of displaced endometrial tissue, ectopic cell survival, angiogenesis, fibrosis, neuroimmune sensitization, pain, and impaired reproductive function. These findings support an immunometabolic model in which macrophage plasticity drives lesion establishment, progression, neuroangiogenesis, pain, and infertility. Therapeutically, targeting macrophage polarization and metabolism—via glycolytic and mitochondrial pathways, lactate signaling, or epitranscriptomic regulators—may restore immune homeostasis and limit disease progression. Further translational studies are needed to validate biomarkers and develop macrophage-directed interventions.