Macrophages in endometriosis: key roles and emerging therapeutic opportunities—a narrative review

Wang et al. Reproductive Biology and Endocrinology https://doi.org/10.1186/s12958-025-01471-3 (2025) 23:134 Reproductive Biology and Endocrinology Open Access REVIEW Macrophages in endometriosis: key roles and emerging therapeutic opportunities—a narrative review Xiaorong Wang1, Ning Wu1 and Qing Xue1* Abstract Background Endometriosis is a chronic gynecological disorder affecting approximately 10% of women of reproductive age. It commonly presents with pelvic pain, dysmenorrhea, and infertility, imposing substantial physical, psychological, and social burdens. Current therapeutic options, such as surgical intervention and hormonal suppression, are constrained by adverse effects and high recurrence rates. Growing evidence implicates immune dysregulation, particularly of macrophages, in the pathophysiology of endometriosis. Main body This narrative review synthesizes foundational and clinical research on macrophages in endometriosis and integrates emerging evidence from single-cell RNA sequencing and spatial transcriptomics to refine current models of macrophage heterogeneity, ontogeny, and therapeutic opportunities. In endometriosis, macrophages adopt heterogeneous, context-dependent states rather than a simple binary pattern. Lesions contain macrophage populations that, through cytokines, chemokines, and growth factors, are implicated in chronic inflammation, impaired clearance of cellular debris, angiogenesis, neuroimmune interactions, extracellular-matrix remodeling, and fibrosis. These immune-mediated mechanisms support lesion survival and are thought to exacerbate symptoms. Recent studies have highlighted several therapeutic strategies aimed at modulating macrophage behavior, including the inhibition of their recruitment to ectopic sites, reprogramming of their functional phenotypes from pro-inflammatory to pro-resolving states, and targeting macrophage-related signaling pathways and immune checkpoints. These approaches are currently under preclinical and clinical investigation and hold promise for reducing disease recurrence and minimizing systemic side effects. Conclusion Macrophages are emerging as central players in the initiation and progression of endometriosis through their contributions to inflammation, lesion maintenance, and fibrogenesis. Targeting macrophage-mediated pathways offers a novel and potentially effective direction for immunomodulatory therapies. A deeper understanding of macrophage plasticity and function within the endometriotic milieu may pave the way for the development of more precise and durable treatment strategies to improve clinical outcomes. Keywords Endometriosis, Macrophages, Immune microenvironment, Single-cell RNA sequencing, Spatial transcriptomics, Immunotherapy *Correspondence: Qing Xue 1 Reproductive Medicine Center, Department of Obstetrics and Gynecology, Peking University First Hospital, No. 1 Xi’anmen Street, Xicheng District, Beijing 100034, China © The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creati vecommons.org/licenses/by-nc-nd/4.0/. Wang et al. Reproductive Biology and Endocrinology (2025) 23:134 Background Endometriosis (EM) is a chronic estrogen-dependent inflammatory disorder characterized by the ectopic implantation, proliferation, infiltration, and cyclic shedding of the functional layer of endometrial glandular and stromal tissue outside the uterine cavity [1, 2]. This condition affects approximately 10% of women of reproductive age worldwide, significantly impairing their quality of life and fertility [1, 3, 4]. Common symptoms include pelvic pain, dysmenorrhea, and infertility, but diagnosis is frequently delayed because of the presence of asymptomatic lesions and the need for surgical confirmation [5]. Current treatments primarily rely on surgical intervention and hormonal therapies. However, surgery carries high recurrence rates, while pharmacological interventions often induce hypoestrogenic side effects, underscoring the urgent need for novel therapeutic approaches [6, 7]. Despite extensive research, the precise etiology of endometriosis remains unresolved. Several theories have been proposed, including Sampson’s retrograde menstruation theory, coelomic metaplasia, and lymphatic or vascular dissemination [8, 9]. Among these, the retrograde menstruation theory, suggested by Sampson in 1921, posits that viable endometrial cells reflux into the peritoneal cavity during menstruation, leading to implantation [10]. However, 76–90% of healthy women also experience retrograde menstruation without developing the disease, indicating that additional factors, such as immune dysregulation, a hyperestrogenic environment, and enhanced inflammatory responses, contribute to disease initiation and progression [1, 11]. Recent research increasingly highlights immune dysfunction as a key contributor to the pathogenesis of endometriosis, with macrophages playing a central role in disease progression. A compromised immune response, characterized by impaired cytotoxicity and phagocytic capacity, fails to effectively eliminate ectopic endometrial cells, creating a permissive environment for lesion persistence [12]. Dysregulated activation of both innate and adaptive immunity leads to excessive production of inflammatory mediators and cytokines, further supporting the establishment and growth of ectopic lesions [13]. Compared to normal endometrium, endometriotic lesions exhibit an altered immune landscape, prominently marked by an increased presence and altered function of macrophages [14]. These macrophages display abnormal distribution and activation, encompassing subsets with pro-inflammatory features— such as secretion of monocyte chemoattractant protein-1 (MCP-1) and production of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)—that amplify local inflammation, as well as subsets with immunoregulatory profiles that facilitate tissue repair and immune evasion Page 2 of 19 [15, 16]. This functional plasticity allows macrophages to participate in multiple stage (...truncated)