Immune cells driving fibrosis in endometriosis: mechanisms and therapeutic implications

TAN Jiarong; OUYANG Zhuqing; QIN Hongzhe; SHEN Fujin

doi:10.14188/j.1671-8852.2026.1171

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Immune cells driving fibrosis in endometriosis: mechanisms and therapeutic implications

更新时间：2026-10-15

- Immune cells driving fibrosis in endometriosis: mechanisms and therapeutic implications
- Medical Journal of Wuhan University Pages: 1-10(2026)
- 作者机构：
  
  武汉大学人民医院妇产科湖北武汉 430060
- 作者简介：
- 基金信息：
- DOI：10.14188/j.1671-8852.2026.1171
  CLC： R711.71
- Online First：15 October 2026，
- 稿件说明：
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TAN Jiarong, OUYANG Zhuqing, QIN Hongzhe, et al. Immune cells driving fibrosis in endometriosis: mechanisms and therapeutic implications[J/OL]. Medical Journal of Wuhan University, 2026, 1-10.
DOI：

TAN Jiarong, OUYANG Zhuqing, QIN Hongzhe, et al. Immune cells driving fibrosis in endometriosis: mechanisms and therapeutic implications[J/OL]. Medical Journal of Wuhan University, 2026, 1-10. DOI： 10.14188/j.1671-8852.2026.1171.

摘要

子宫内膜异位症（EMs）是一种以慢性炎症、异常免疫应答及进行性纤维化为主要特征的雌激素依赖性疾病。近年来研究表明，纤维化不仅是EMs病灶成熟和疾病进展的重要病理特征，也是导致盆腔粘连、慢性盆腔痛及不孕等临床结局的重要基础。已有研究证实，免疫细胞异常活化及免疫微环境失衡贯穿EMs纤维化全过程。其中，巨噬细胞、肥大细胞、中性粒细胞、自然杀伤细胞及不同T细胞亚群通过分泌炎症及促纤维化因子，调控上皮⁃间质转化（EMT）、成纤维细胞⁃肌成纤维细胞转化（FMT）、细胞外基质（ECM）沉积及组织重塑等多种途径，共同促进病灶纤维化形成。随着单细胞转录组、空间转录组等新技术的发展，EMs免疫微环境及免疫细胞间相互作用机制得到进一步阐明，也为免疫调控治疗提供了新的理论基础。目前，靶向炎症因子、巨噬细胞重编程、免疫检查点及免疫耐受等策略已展现出一定的抗纤维化潜力。本文围绕EMs纤维化过程中不同免疫细胞的作用及其分子机制进行综述，并总结近年来免疫调控治疗的研究进展，以期为EMs抗纤维化治疗及精准免疫干预提供新的研究思路。

Abstract

Endometriosis (EMs) is an estrogen⁃dependent disease characterized primarily by chronic inflammation

abnormal immune responses

and progressive fibrosis. Recent studies have demonstrated that fibrosis not only serves as a critical pathological feature of lesion maturation and disease progression in EMs but also constitutes a fundamental basis for clinical outcomes such as pelvic adhesions

chronic pelvic pain

and infertility. Growing evidence suggests that abnormal activation of immune cells and dysregulation of the immune microenvironment persist throughout the entire fibrotic process of EMs. Macrophages

mast cells

neutrophils

natural killer cells

and various T⁃cell subsets contribute to fibrosis formation by secreting pro⁃inflammatory and pro⁃fibrotic factors

regulating multiple pathways

including epithelial⁃mesenchymal transition (EMT)

fibroblast⁃myofibroblast transformation (FMT)

extracellular matrix (ECM) deposition

and tissue remodeling. Advances in single⁃cell transcriptomics and spatial transcriptomics have further elucidated the mechanisms of immune microenvironment interactions and intercellular communication within EMs

providing novel theoretical foundations for immunomodulatory therapies. Current strategies targeting inflammatory cytokines

macrophage reprogramming

immune checkpoints

and immune tolerance have shown certain anti⁃fibrotic potential. This review examines the roles and molecular mechanisms of various immune cells during EMs fibrosis and summarizes recent progress in immunomodulatory therapies

aiming to offer new insights for anti⁃fibrotic treatment and precision immunotherapy in EMs.

关键词

Keywords

references

AS⁃SANIE S , MACKENZIE S C , MORRISON L , et al . Endometriosis: A review [J ] . JAMA , 2025 , 334 ( 1 ): 64 ⁃ 78 .

WANG M H , CHEN J H , QI X Y , et al . Global prevalence of adenomyosis and endometriosis: A systematic review and meta⁃analysis [J ] . Reprod Biol Endocrinol , 2025 , 23 ( 1 ): 148 .

BULUN S E . Endometriosis and ovulatory menstruation: Beyond the Sampson principle [J ] . J Clin Invest , 2025 , 135 ( 13 ): e188787 .

VANNUCCINI S , CLEMENZA S , ROSSI M , et al . Hormonal treatments for endometriosis: The endocrine background [J ] . Rev Endocr Metab Disord , 2022 , 23 ( 3 ): 333 ⁃ 355 .

SHIFON S , TYRINOVA T , VERETELNIKOVA T , et al . Endometriosis as an immune⁃mediated disease: Pathogenetic mechanisms and therapeutic strategies [J ] . Front Immunol , 2025 , 16 : 1727183 .

WANG Y , NICHOLES K , SHIH I M . The origin and pathogenesis of endometriosis [J ] . Annu Rev Pathol , 2020 , 15 : 71 ⁃ 95 .

GARMENDIA J V , DE SANCTIS C V , HAJDÚCH M , et al . Endometriosis: An immunologist's perspective [J ] . Int J Mol Sci , 2025 , 26 ( 11 ): 5193 .

VISSERS G , GIACOMOZZI M , VERDURMEN W , et al . The role of fibrosis in endometriosis: A systematic review [J ] . Hum Reprod Update , 2024 , 30 ( 6 ): 706 ⁃ 750 .

BURNEY R O . Fibrosis as a molecular hallmark of endometriosis pathophysiology [J ] . Fertil Steril , 2022 , 118 ( 1 ): 203 ⁃ 204 .

CHEN S , LIU Y , ZHONG Z , et al . Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives [J ] . Front Immunol , 2023 , 14 : 1134663 .

ABRAMIUK M , GRYWALSKA E , MAŁKOWSKA P , et al . The role of the immune system in the development of endometriosis [J ] . Cells , 2022 , 11 ( 13 ): 2028 .

DUAN J , LIU X , WANG H , et al . The M2a macrophage subset may be critically involved in the fibrogenesis of endometriosis in mice [J ] . Reprod Biomed Online , 2018 , 37 ( 3 ): 254 ⁃ 268 .

NIE M F , XIE Q , WU Y H , et al . Serum and ectopic endometrium from women with endometriosis modulate macrophage M1/M2 polarization via the Smad2/Smad3 pathway [J ] . J Immunol Res , 2018 , 2018 : 6285813 .

WANG B , HU L , ZHANG Z , et al . UBE2S⁃mediated deubiquitination of GLUT1 via USP10 regulates glucose metabolic reprogramming and immune microenvironment to promote fibrosis in endometriosis [J ] . J Transl Med , 2025 , 23 ( 1 ): 1383 .

YANG P , WANG T , MIAO Y , et al . SLC25A1⁃mediated cholesterol accumulation promotes endometriosis progression by enhancing endometrial stromal cell proliferation, invasion, and M2 macrophage polarization [J ] . Int J Biol Sci , 2026 , 22 ( 1 ): 466 ⁃ 480 .

BERNACCHIONI C , CAPEZZUOLI T , VANNUZZI V , et al . Sphingosine 1⁃phosphate receptors are dysregulated in endometriosis: Possible implication in transforming growth factor β⁃induced fibrosis [J ] . Fertil Steril , 2021 , 115 ( 2 ): 501 ⁃ 511 .

ONO Y , KAWAKITA T , YOSHINO O , et al . Sphingosine 1⁃phosphate (S1P) in the peritoneal fluid skews M2 macrophage and contributes to the development of endometriosis [J ] . Biomedicines , 2021 , 9 ( 11 ): 1519 .

CHEN S M , LIU Y K , MA X Q , et al . Creatine promotes endometriosis progression by inducing M2 polarization of peritoneal macrophages [J ] . Reproduction , 2025 , 169 ( 3 ): e240278 .

SUN S G , GUO J J , QU X Y , et al . The extracellular vesicular pseudogene LGMNP1 induces M2⁃like macrophage polarization by upregulating LGMN and serves as a novel promising predictive biomarker for ovarian endometriosis recurrence [J ] . Hum Reprod , 2022 , 37 ( 3 ): 447 ⁃ 465 .

HENLON Y , PANIR K , MCINTYRE I , et al . Single⁃cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche [J ] . Proc Natl Acad Sci U S A , 2024 , 121 ( 38 ): e2405474121 .

LV H , LIU B , DAI Y , et al . TET3⁃overexpressing macrophages promote endometriosis [J ] . J Clin Invest , 2024 , 134 ( 21 ): e181839 .

ZHONG Y , HUANG X , LI Y , et al . TGFB1/SMAD3⁃driven macrophage⁃myofibroblast transition promotes fibrosis progression in endometriosis [J ] . Molecular Human Reproduction , 2025 , 31 ( 4 ): gaaf051 .

MIKHALEV S , KOSTIN A , KURTSER M , et al . Spatial phenotype of the mast cell population in endometritis of various severities [J ] . Cells , 2025 , 15 ( 1 ): 38 .

GUO X , XU X , LI T , et al . NLRP3 inflammasome activation of mast cells by estrogen via the nuclear⁃initiated signaling pathway contributes to the development of endometriosis [J ] . Front Immunol , 2021 , 12 : 749979 .

ATIAKSHIN D , PATSAP O , KOSTIN A , et al . Mast cell tryptase and carboxypeptidase A3 in the formation of ovarian endometrioid cysts [J ] . Int J Mol Sci , 2023 , 24 ( 7 ): 6498 .

GARCIA GARCIA J M , VANNUZZI V , DONATI C , et al . Endometriosis: Cellular and molecular mechanisms leading to fibrosis [J ] . Reprod Sci , 2023 , 30 ( 5 ): 1453 ⁃ 1461 .

GOLINSKA M , WOŁYNIAK M , KULESZA P , et al . Neuroinflammation is responsible for pain in endometriosis–targeting the JAK⁃STAT pathway and mast cell activation [J ] . Front Immunol , 2025 , 16 : 1621178 .

XIAO F , LIU X , GUO S W . Interleukin⁃33 derived from endometriotic lesions promotes fibrogenesis through inducing the production of profibrotic cytokines by regulatory T cells [J ] . Biomedicines , 2022 , 10 ( 11 ): 2893 .

SIKORA J , SMYCZ‑KUBAŃSKA M , MIELCZAREK‑PALACZ A , et al . The involvement of multifunctional TGF‑β and related cytokines in pathogenesis of endometriosis [J ] . Immunol Lett , 2018 , 201 : 31 ‑ 37 .

KISOVAR A , BECKER C M , GRANNE I , et al . The role of CD8 + T cells in endometriosis: A systematic review [J ] . Front Immunol , 2023 , 14 : 1225639 .

MA J , ZHANG L , ZHAN H , et al . Single⁃cell transcriptomic analysis of endometriosis provides insights into fibroblast fates and immune cell heterogeneity [J ] . Cell Biosci , 2021 , 11 ( 1 ): 125 .

REIS J L , ROSA N N , ÂNGELO⁃DIAS M , et al . Natural killer cell receptors and endometriosis: A systematic review [J ] . Int J Mol Sci , 2023 , 24 ( 1 ): 331 .

HUANG B , WEI Y , YANG R , et al . 9902 single⁃cell RNA sequencing reveals macrophage⁃fibroblast transformation mode in endometriosis [J ] . J Minim Invasive Gynecol , 2023 , 30( 11 , Supplement ): S92 ⁃S93.

XU X , LI J , LIN H , et al . The role of TGF⁃β superfamily in endometriosis: a systematic review [J ] . Frontiers in Immunology , 2025 , 16 : 1638604 .

TAN Y , FLYNN W F , SIVAJOTHI S , et al . Single⁃cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues [J ] . Nat Cell Biol , 2022 , 24 ( 8 ): 1306 ⁃ 1318 .

WILSON T R , PETERSON K R , MORRIS S A , et al . Neutrophils initiate proinflammatory immune responses in early endometriosis lesion development [J ] . JCI Insight , 2025 , 10 ( 5 ): e186133 .

GIRLING J E . Harnessing the inflammatory processes in endometriosis [J ] . Nat Rev Endocrinol , 2024 , 20 ( 2 ): 69 ⁃ 70 .

ANCHAN M M , DUTTA R . Reframing endometriosis: Interplay of NETs, macrophages, and lymphocytes at the crossroads of disease progression, infertility, and malignant transformation [J ] . Am J Reprod Immunol , 2025 , 94 ( 5 ): e70179 .

WU X , YANG Y . Neutrophil extracellular traps (NETs) and fibrotic diseases [J ] . Int Immunopharmacol , 2024 , 133 : 112085 .

LI J L , YAO B , CHU L Y , et al . Targeting the IL‑17C‑M2 macrophage axis ameliorates fibrosis in endometriosis through MAPK/ERK signaling [J ] . J Transl Med , 2026 , 24 ( 1 ): 1015 .

PIRIYEV E , SCHIERMEIER S , RÖMER T . Hormonal treatment of endometriosis: A narrative review [J ] . Pharmaceuticals , 2025 , 18 ( 4 ): 588 .

EL⁃ZAYADI A A , MOHAMED S A , ARAFA M , et al . Anti⁃IL⁃6 receptor monoclonal antibody as a new treatment of endometriosis [J ] . Immunol Res , 2020 , 68 ( 6 ): 389 ⁃ 397 .

FALCONER H , MWENDA J M , CHAI D C , et al . Treatment with anti⁃TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon [J ] . Hum Reprod , 2006 , 21 ( 7 ): 1856 ⁃ 1862 .

LIU W , SHEN J , YOU J , et al . A novel fertility⁃sparing nanocomposite for endometriosis treatment via oxidative stress and inflammation alleviation [J ] . Mater Today Bio , 2025 , 33 : 102041 .

ZHANG M , YE Y , CHEN Z , et al . Targeting delivery of mifepristone to endometrial dysfunctional macrophages for endometriosis therapy [J ] . Acta Biomater , 2024 , 189 : 505 ⁃ 518 .

WU N , HAN Z , LV W , et al . Reprogramming peritoneal macrophages with outer membrane vesicle⁃coated PLGA nanoparticles for endometriosis prevention [J ] . Biomaterials , 2025 , 319 : 123198 .

REIS J L , ROSA N N , MARTINS C , et al . The role of NK and T cells in endometriosis [J ] . Int J Mol Sci , 2024 , 25 ( 18 ): 10141 .

WANG X , WU N , XUE Q . Macrophages in endometriosis: key roles and emerging therapeutic opportunities–A narrative review [J ] . Reprod Biol Endocrinol , 2025 , 23 ( 1 ): 134 .

DAI Y , YE Z , LIN X , et al . Immunopathological insights into endometriosis: From research advances to future treatments [J ] . Semin Immunopathol , 2025 , 47 ( 1 ): 31 .

BUTTERFIELD L H , NAJJAR Y G . Immunotherapy combination approaches: Mechanisms, biomarkers and clinical observations [J ] . Nat Rev Immunol , 2024 , 24 ( 6 ): 399 ⁃ 416 .

BURNS K A , PETERSE D , APPLEYARD C B , et al . WERF endometriosis phenome and biobanking harmonisation project for experimental models in endometriosis research (EPHect⁃EM⁃homologous): Homologous rodent models [J ] . Mol Hum Reprod , 2025 , 31 ( 3 ): gaaf021 .

VIGANÒ P , CAPRARA F , GIOLA F , et al . Is retrograde menstruation a universal, recurrent, physiological phenomenon? A systematic review of the evidence in humans and non⁃human primates [J ] . Hum Reprod Open , 2024 , 2024 ( 3 ): hoae045 .

HE F , ZU S , LIN Y , et al . Integrated single⁃cell and spatial transcriptomics reveal divergent immunological and stromal programs in peritoneal versus ovarian endometriosis [J ] . BMC Women's Health , 2026 , 26 ( 1 ): 278 .

AHMED M , RIAZ U , LV H , et al . Nicotinamide mononucleotide restores NAD + levels to alleviate LPS⁃induced inflammation via the TLR4/NF⁃κB/MAPK signaling pathway in mice granulosa cells [J ] . Antioxidants , 2025 , 14 ( 1 ): 39 .

ARCE VARGAS F , FURNESS A J S , LITCHFIELD K , et al . Fc effector function contributes to the activity of human anti⁃CTLA⁃4 antibodies [J ] . Cancer Cell , 2018 , 33 ( 4 ): 649 ⁃ 663 .e4.

BOU ZERDAN M , KFOURY B , AOUN E , et al . Pregnancy outcomes after in utero exposure to immune checkpoint inhibitors [J ] . Curr Oncol , 2026 , 33 ( 6 ): 318 .

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