{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:00:31Z","timestamp":1790773231375,"version":"4.1.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Endometriosis and adenomyosis are commonly managed through endocrine suppression, analgesia and surgery, yet these approaches do not fully explain persistent pain, recurrence, fibrotic remodeling or variable treatment response. A growing body of immune and single-cell evidence supports a complementary view in which hormone-permissive tissue injury licenses macrophage-centered inflammatory, fibrotic and neuroimmune programs. This mini review reframes both disorders as related, but not identical, immune-fibrotic conditions and identifies tractable immunopharmacological nodes. We discuss macrophage plasticity, monocyte recruitment, cytokine and chemokine amplification, inflammasome signaling, TGF-\u03b2-driven fibrosis, oxidative and metabolic stress, neuroimmune pain signaling and targeted delivery. We argue that non-hormonal therapy should not be developed simply as an alternative to hormonal suppression. Instead, it should be tested as a phenotype-guided strategy that matches dominant immune-fibrotic programs to mechanism-based interventions while preserving reproductive safety. This framework highlights the need for biomarker-informed patient selection, compartment-specific endpoints and early attention to fertility-compatible translational design.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1925057","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T08:53:23Z","timestamp":1789980803000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Macrophage-centered immune-fibrotic persistence in endometriosis and adenomyosis: non-hormonal immunopharmacological targets"],"prefix":"10.3389","volume":"17","author":[{"given":"Chan","family":"Yu","sequence":"first","affiliation":[{"name":"Department of Women\u2019s Health and Rehabilitation, Huadu District Maternal and Child Health Hospital","place":["Guangzhou, Guangdong, China"]},{"name":"Department of Gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danmiao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, Baiyun District Jiahe Street Community Health Service Center","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"An","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gynecology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(21)00389-5","article-title":"Endometriosis is a chronic systemic disease: clinical challenges and novel innovations","volume":"397","author":"Taylor","year":"2021","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-023-01957-7","article-title":"Current medical therapy for adenomyosis: from bench to bedside","volume":"83","author":"Etrusco","year":"2023","journal-title":"Drugs"},{"key":"B3","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1093\/humupd\/dmz049","article-title":"Diagnosing adenomyosis: an integrated clinical and imaging approach","volume":"26","author":"Chapron","year":"2020","journal-title":"Hum Reprod Update"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoac009","article-title":"ESHRE guideline: endometriosis","volume":"2022","author":"Becker","year":"2022","journal-title":"Hum Reprod Open"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(22)00622-5","article-title":"Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2)","volume":"399","author":"Giudice","year":"2022","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1093\/humupd\/dmaa033","article-title":"Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis","volume":"27","author":"Zakhari","year":"2021","journal-title":"Hum Reprod Update"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmae023","article-title":"The role of fibrosis in endometriosis: a systematic review","volume":"30","author":"Vissers","year":"2024","journal-title":"Hum Reprod Update"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1111\/aogs.13156","article-title":"Progesterone resistance in endometriosis: origins, consequences and interventions","volume":"96","author":"Patel","year":"2017","journal-title":"Acta Obstetricia Gynecologica Scandinavica"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-021-09666-w","article-title":"Hormonal treatments for endometriosis: the endocrine background","volume":"23","author":"Vannuccini","year":"2022","journal-title":"Rev Endocr Metab Disord"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24086992","article-title":"Progesterone resistance in endometriosis: current evidence and putative mechanisms","volume":"24","author":"Zhang","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmz018","article-title":"The endometrial immune environment of women with endometriosis","volume":"25","author":"Vallv\u00e9-Juanico","year":"2019","journal-title":"Hum Reprod Update"},{"key":"B12","doi-asserted-by":"publisher","first-page":"5193","DOI":"10.20944\/preprints202504.1726.v1","article-title":"Endometriosis: an immunologist\u2019s perspective","volume":"26","author":"Garmendia","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.adk8230","article-title":"Nociceptor-to-macrophage communication through CGRP\/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice","volume":"16","author":"Fattori","year":"2024","journal-title":"Sci Transl Med"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00007","article-title":"Endometriosis-associated macrophages: origin, phenotype, and function","volume":"11","author":"Hogg","year":"2020","journal-title":"Front Endocrinol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioaf164","article-title":"Endometriosis: new insights and opportunities for relief of symptoms","volume":"113","author":"Saunders","year":"2025","journal-title":"Biol Reprod"},{"key":"B16","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1007\/s00281-025-01040-1","article-title":"Perturbations of the endometrial immune microenvironment in endometriosis and adenomyosis: their impact on reproduction and pregnancy","volume":"47","author":"Shi","year":"2025","journal-title":"Semin Immunopathology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1186\/s12958-025-01471-3","article-title":"Macrophages in endometriosis: key roles and emerging therapeutic opportunities\u2014a narrative review","volume":"23","author":"Wang","year":"2025","journal-title":"Reprod Biol Endocrinol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1093\/humupd\/dmaa038","article-title":"Immunological changes associated with adenomyosis: a systematic review","volume":"27","author":"Bourdon","year":"2021","journal-title":"Hum Reprod Update"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioae032","article-title":"The pathogenesis of endometriosis and adenomyosis: insights from single-cell RNA sequencing","volume":"110","author":"Li","year":"2024","journal-title":"Biol Reprod"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.xgen.2024.100737","article-title":"Single-cell and spatial transcriptomic profiling revealed niche interactions sustaining growth of endometriotic lesions","volume":"5","author":"Liu","year":"2025","journal-title":"Cell Genomics"},{"key":"B21","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1111\/imm.13574","article-title":"Ectopic endometriotic stromal cells-derived lactate induces M2 macrophage polarization via Mettl3\/Trib1\/ERK\/STAT3 signalling pathway in endometriosis","volume":"168","author":"Gou","year":"2023","journal-title":"Immunology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1172\/jci181839","article-title":"TET3-overexpressing macrophages promote endometriosis","volume":"134","author":"Lv","year":"2024","journal-title":"J Clin Invest"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13841","article-title":"Macrophage polarization in adenomyosis: a review","volume":"91","author":"Qiu","year":"2024","journal-title":"Am J Reprod Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-025-01944-1","article-title":"Endometrial mesenchymal stem cell-derived exosomal miR-4669 promotes EMT in adenomyosis by inducing M2 macrophage polarization via the DUSP6\/ERK pathway","volume":"32","author":"Qiu","year":"2025","journal-title":"Reprod Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2024.122902","article-title":"MCP-1 exerts the inflammatory response via ILK activation during endometriosis pathogenesis","volume":"353","author":"Soni","year":"2024","journal-title":"Life Sci"},{"key":"B26","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1186\/s12974-017-0828-3","article-title":"Macrophage and nerve interaction in endometriosis","volume":"14","author":"Wu","year":"2017","journal-title":"J Neuroinflamm"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2022.103649","article-title":"NLRP3 activated macrophages promote endometrial stromal cells migration in endometriosis","volume":"152","author":"Zhou","year":"2022","journal-title":"J Reprod Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gaaf051","article-title":"TGFB1\/SMAD3-driven macrophage\u2013myofibroblast transition promotes fibrosis progression in endometriosis","volume":"31","author":"Zhong","year":"2025","journal-title":"Mol Hum Reprod"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00404-018-4754-0","article-title":"The role of complement components C1q, MBL and C1 inhibitor in pathogenesis of endometriosis","volume":"297","author":"Sikora","year":"2018","journal-title":"Arch Gynecology Obstetrics"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1405597","article-title":"Proangiogenic properties of complement protein C1q can contribute to endometriosis","volume":"15","author":"Agostinis","year":"2024","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00402","article-title":"Complement, C1q, and C1q-related molecules regulate macrophage polarization","volume":"5","author":"Bohlson","year":"2014","journal-title":"Front Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.molimm.2009.04.027","article-title":"The role of the anaphylatoxins in health and disease","volume":"46","author":"Klos","year":"2009","journal-title":"Mol Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dei154","article-title":"Expression of interleukin-8 and monocyte chemotactic protein-1 in adenomyosis","volume":"20","author":"Ulukus","year":"2005","journal-title":"Hum Reprod"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1186\/s12958-022-00924-3","article-title":"Effectiveness of NLRP3 inhibitor as a non-hormonal treatment for ovarian endometriosis","volume":"20","author":"Murakami","year":"2022","journal-title":"Reprod Biol Endocrinol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/aji.70132","article-title":"ATP\/P2X4 regulates inflammation and oxidative stress in endometriosis through NLRP3 inflammasome\u2013dependent mechanisms","volume":"94","author":"Wu","year":"2025","journal-title":"Am J Reprod Immunol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.fertnstert.2011.11.005","article-title":"Dienogest inhibits aromatase and cyclooxygenase-2 expression and prostaglandin E2 production in human endometriotic stromal cells in spheroid culture","volume":"97","author":"Yamanaka","year":"2012","journal-title":"Fertility Sterility"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2016.08.011","article-title":"Involvement of NADPH oxidase and NF-\u03baB activation in CXCL1 induction by vascular endothelial growth factor in human endometrial epithelial cells of patients with adenomyosis","volume":"118","author":"Lai","year":"2016","journal-title":"J Reprod Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0089742","article-title":"Lipoxin A4 prevents the progression of de novo and established endometriosis in a mouse model by attenuating prostaglandin E2 production and estrogen signaling","volume":"9","author":"Kumar","year":"2014","journal-title":"PloS One"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/med.21802","article-title":"Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: a review","volume":"41","author":"Hung","year":"2021","journal-title":"Med Res Rev"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/biom12111654","article-title":"Emerging drug targets for endometriosis","volume":"12","author":"Dolmans","year":"2022","journal-title":"Biomolecules"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s43032-022-01083-x","article-title":"Endometriosis: cellular and molecular mechanisms leading to fibrosis","volume":"30","author":"Garcia Garcia","year":"2023","journal-title":"Reprod Sci"},{"key":"B42","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41420-022-00821-z","article-title":"Endometrial stromal cell ferroptosis promotes angiogenesis in endometriosis","volume":"8","author":"Li","year":"2022","journal-title":"Cell Death Discov"},{"key":"B43","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1007\/s00109-025-02528-x","article-title":"Targeting ferroptosis for the treatment of female reproductive system disorders","volume":"103","author":"Ye","year":"2025","journal-title":"J Mol Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1613334","article-title":"Endometriosis-associated infertility: multi-omics insights into pathogenesis and precision therapeutics","volume":"16","author":"Ou","year":"2025","journal-title":"Front Endocrinol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202300907","article-title":"Endometriosis in the era of precision medicine and impact on sexual and reproductive health across the lifespan and in diverse populations","volume":"37","author":"Giudice","year":"2023","journal-title":"FASEB J"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1039\/d4bm01506a","article-title":"A cRGD-modified liposome for targeted delivery of artesunate to inhibit angiogenesis in endometriosis","volume":"13","author":"Ma","year":"2025","journal-title":"Biomater Sci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.4900569","article-title":"Neutrophil hitchhiking liposomal drugs for starvation therapy in endometriosis","volume":"15","author":"Zhou","year":"2025","journal-title":"Theranostics"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01873-w","article-title":"An integrated single-cell reference atlas of the human endometrium","volume":"56","author":"Mare\u010dkov\u00e1","year":"2024","journal-title":"Nat Genet"},{"key":"B49","doi-asserted-by":"publisher","first-page":"11539","DOI":"10.1038\/s41467-025-66706-8","article-title":"Single-cell and spatially resolved omics reveal transcriptional and metabolic signatures of ovarian endometriomas","volume":"16","author":"Qi","year":"2025","journal-title":"Nat Commun"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2025.12.042","article-title":"Spatial and single-cell transcriptomics landscape of adenomyosis","author":"Yang","year":"2025","journal-title":"J Adv Res"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1925057\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:33:56Z","timestamp":1790771636000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1925057\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2026.1925057"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1925057","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]},"article-number":"1925057"}}