Research Advances in the Endometriotic Microenvironment: Synergistic Immune-Inflammatory-Angiogenic Interactions and their Therapeutic Translation

Endometriosis (EM) is a chronic inflammatory disorder characterized by the ectopic growth of endometrial-like tissue outside the uterine cavity. Its pathogenesis is closely linked to an imbalanced immune–inflammatory–angiogenic microenvironment. Core pathological features include immune suppression (e.g., M2 macrophage polarization, regulatory T cell increase), chronic inflammation (e.g., elevated IL-6, TNF-α, NF-κB/NLRP3 activation), and hypoxia-driven aberrant angiogenesis via the VEGF/HIF-1α axis. These components interact through shared molecular pathways—such as HIF-1α and NF-κB synergistically upregulating VEGF—forming a self-sustaining feedback loop that promotes lesion growth, fibrosis, pain, and infertility. Recent studies have explored microenvironment-targeted therapies (e.g., immune checkpoint blockade, anti-angiogenics), though most remain preclinical. Challenges include optimizing treatment timing, overcoming resistance, and patient heterogeneity. Future research should leverage multi-omics and organoid models to decode EM microenvironment dynamics and advance precision medicine. Similar content being viewed by others Data Availability Not applicable. This review synthesizes information from previously published studies, and no new datasets were generated.

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We sincerely thank our colleagues at Shandong Provincial Hospital Affiliated to Shandong First Medical University for their valuable support. Funding The National Key R&D Program of China (2022YFC2704000); the Special foundation for Taishan Scholars (No. tstp20230657); the Major Basic Research of Natural Science Foundation of Shandong (ZR2021ZD34); the National Natural Science Foundation of China (grant numbers 82371653 and 82071621); and General Project of Shandong Natural Science Foundation ZR2023MH177. Author information Authors and Affiliations Contributions Liu Xiaoxuan: Writing– original draft. Wang Guoyun: Writing– review and editing. Corresponding author Ethics declarations Ethics Approval and Consent to Participate Not applicable. Consent for Publication Not applicable Competing Interests The authors declare that there are no conflicts of interest related to this article. Additional information Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. About this article Cite this article Liu, X., Wang, G. Research Advances in the Endometriotic Microenvironment: Synergistic Immune–Inflammatory–Angiogenic Interactions and their Therapeutic Translation. Reprod. Sci. 33, 1–11 (2026). https://doi.org/10.1007/s43032-025-02017-z Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s43032-025-02017-z