Endometriosis from Initiation to Innovation: Immune Microenvironments, Clonal Lesion Biology, and the Emerging Therapeutic Pipeline

Bindu Santhamma, Santhamma B, Jessica Chacon, Chacon J, Deemer E, Eva Deemer, Dorota Stary, Stary D, Shayla A Hernandez, Hernandez SA, Ramadevi Subramani, Subramani R, Rajkumar Lakshmanaswamy, Lakshmanaswamy R, Nickisch KJ, Klaus Nickisch, Klaus J Nickisch, Surinder Batra, Batra S, Hareesh B. Nair, Nair HB
Cancer letters · 2026 · pp. 218845 · doi:10.1016/j.canlet.2026.218845 · PMID:42762962 · W7213646046
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Abstract

Endometriosis is a chronic, estrogen-dependent inflammatory disease that, despite its benign histology, displays several cancer-relevant features, including clonal expansion, somatic alteration-associated lesion evolution, tissue invasion, apoptosis resistance, immune evasion, angiogenesis, fibrosis, and metabolic adaptation. These features are particularly important in ovarian endometriosis, where recurrent hemorrhage, iron-driven oxidative stress, and chronic inflammatory remodeling may promote malignant transformation. This review examines endometriosis through an oncologic framework by integrating current evidence on disease initiation, clonal lesion evolution, and the peritoneal, ovarian, and deep-infiltrating microenvironments. We discuss how epithelial, stromal, immune, endothelial, mesothelial, and neural components cooperate to support lesion survival, dissemination, vascularization, fibrosis, neuroinflammation, and treatment resistance. Particular attention is given to cancer-associated molecular programs, including PI3K-AKT-mTOR, RAS-MAPK, WNT/β-catenin, hypoxia, oxidative-stress, inflammatory, and epigenetic signaling, and their relationship to endometriosis-associated ovarian cancer. We also critically evaluate animal models, organoids, three-dimensional scaffolds, and microfluidic systems for their ability to reproduce lesion heterogeneity, microenvironmental interactions, therapeutic responses, and malignant progression. Finally, we assess current and emerging therapeutic strategies, emphasizing non-hormonal interventions directed against inflammatory, immune, fibrotic, angiogenic, metabolic, and oncogenic vulnerabilities, together with biomarker-guided and fertility-sparing approaches. Viewing endometriosis as a cancer-relevant inflammatory and clonal disease may reveal actionable mechanisms for precision treatment and interception of endometriosis-associated malignancy.

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