The Role of Immune Cells and Cytokines in the Pathogenesis and Treatment of Genital Endometriosis

Review Article The Role of Immune Cells and Cytokines in the Pathogenesis and Treatment of Genital Endometriosis This work is licensed under a Creative Commons Attribution 4.0 International License. Copyright The authors shall retain the copyright of their work but allow the Publisher to publish, copy, distribute, and convey the work. License Trends in Immunotherapy (TI) publishes accepted manuscripts under Creative Commons Attribution 4.0 International (CC BY 4.0). Authors who submit their papers for publication by TI agree to have the CC BY 4.0 license applied to their work, and that anyone is allowed to reuse the article or part of it free of charge for any purpose, including commercial use. As long as the author and original source are properly cited, anyone may copy, redistribute, reuse, and transform the content. Received: 24 June 2025; Revised: 12 July 2025; Accepted: 8 September 2025; Published: 30 September 2025 Genital endometriosis is a chronic inflammatory condition characterized by immune dysfunction involving both innate and adaptive immunity. Disrupted immune responses, particularly those involving macrophages, dendritic cells, natural killer cells, regulatory T cells, T helper 17 cells, and B-cell-driven autoimmunity, create an environment conducive to ectopic endometrial tissue survival. The cytokine milieu, marked by elevated levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-10, facilitates the interaction between inflammation and immune tolerance, thereby driving disease progression. Current hormonal and surgical treatments offer only temporary or partial symptom relief and fail to address the underlying immunopathogenic mechanisms of the disease. Their limitations, including high recurrence rates, systemic side effects, and insufficient fertility restoration, highlight the need for novel interventions that target specific pathways. Recent advances in immunology and microbiome research have led to promising therapeutic strategies, such as microbiome modulation, precision medicine based on immune phenotyping, and integrative care models that provide personalized and comprehensive treatment. Future research should focus on advancing immune and microbial profiling to guide targeted therapies, validating immunomodulatory approaches, and integrating these methods into clinical practices. By bridging basic research with clinical applications, the field is poised to shift from managing symptoms to altering the disease trajectory, ultimately improving outcomes for women affected by genital endometriosis. Keywords: Genital Endometriosis Immune Dysfunction Macrophages Natural Killer Cells Dendritic CellsReferences - Ozkan, S.; Murk, W.; Arici, A. Endometriosis and Infertility: Epidemiology and Evidence-Based Treatments. Ann. N. Y. Acad. Sci. 2008, 1127, 92–100. - Yoldemir, T. Evaluation and Management of Endometriosis. Climacteric 2023, 26, 248–255. - Sheveleva, T.; Bejenar, V.; Komlichenko, E.; et al. Innovative Approach in Assessing the Role of Neurogenesis, Angiogenesis, and Lymphangiogenesis in the Pathogenesis of External Genital Endometriosis. Gynecol. Endocrinol. 2016, 32, 75–79. - Cramer, D.W.; Missmer, S.A. The Epidemiology of Endometriosis. Ann. N. Y. Acad. Sci. 2002, 955, 11–22. - Salliss, M.E.; Farland, L.V.; Mahnert, N.D.; et al. The Role of Gut and Genital Microbiota and the Estrobolome in Endometriosis, Infertility and Chronic Pelvic Pain. Hum. Reprod. Update 2021, 28, 92–131. - Allaire, C. Endometriosis and Infertility: A Review. J. Reprod. Med. 2006, 51, 164–168. - Halis, G.; Arici, A. Endometriosis and Inflammation in Infertility. Ann. N. Y. Acad. Sci. 2004, 1034, 300–315. - Cao, W.; Fu, X.; Zhou, J.; et al. The Effect of the Female Genital Tract and Gut Microbiome on Reproductive Dysfunction. Biosci. Trends 2024, 17, 458–474. - Oishi, S.; Mekaru, K.; Tanaka, S.E.; et al. Microbiome Analysis in Women with Endometriosis: Does a Microbiome Exist in Peritoneal Fluid and Ovarian Cystic Fluid? Reprod. Med. Biol. 2022, 21, e12441. - Vercellini, P.; Viganò, P.; Somigliana, E.; et al. Endometriosis: Pathogenesis and Treatment. Nat. Rev. Endocrinol. 2014, 10, 261–275. - Zondervan, K.T.; Becker, C.M.; Missmer, S.A. Endometriosis. N. Engl. J. Med. 2020, 382, 1244–1256. - Porpora, M.G.; Brunelli, R.; Costa, G.; et al. A Promise in the Treatment of Endometriosis: An Observational Cohort Study on Ovarian Endometrioma Reduction by N-Acetylcysteine. Evid. Based Complement. Alternat. Med. 2013, 2013, 240702. - Taguchi, A.; Wada-Hiraike, O.; Kawana, K.; et al. Resveratrol Suppresses Inflammatory Responses in Endometrial Stromal Cells Derived from Endometriosis: A Possible Role of the Sirtuin 1 Pathway. J. Obstet. Gynaecol. Res. 2014, 40, 770–778. - Lu, L.; Feng, X.; Wang, R.; et al. Curcumol Inhibits Endometrial Cell Invasion through the NF-κB Pathway in Rats with Endometriosis. Pak. J. Pharm. Sci. 2024, 37, 1493–1504. - Li, Y.; Hung, S.W.; Zhang, R.; et al. Melatonin in Endometriosis: Mechanistic Understanding and Clinical Insight. Nutrients 2022, 14, 4087. - Shigesi, N.; Kvaskoff, M.; Kirtley, S.; et al. The Association between Endometriosis and Autoimmune Diseases: A Systematic Review and Meta-Analysis. Hum. Reprod. Update 2019, 25, 486–503. - Ata, B.; Yildiz, S.; Turkgeldi, E.; et al. The Endobiota Study: Comparison of Vaginal, Cervical and Gut Microbiota between Women with Stage 3/4 Endometriosis and Healthy Controls. Sci. Rep. 2019, 9, 2204. - Fan, D.; Wang, X.; Shi, Z.; et al. Understanding Endometriosis from an Immunomicroenvironmental Perspective. Chin. Med. J. 2023, 136, 1897–1909. - Mechsner, S. Endometriosis, an Ongoing Pain-Step-by-Step Treatment. J. Clin. Med. 2022, 11, 467. - Rafique, S.; Decherney, A.H. Medical Management of Endometriosis. Clin. Obstet. Gynecol. 2017, 60, 485–496. - Streuli, I.; de Ziegler, D.; Santulli, P.; et al. An Update on the Pharmacological Management of Endometriosis. Expert Opin. Pharmacother. 2013, 14, 291–305. - Donnez, J.; Pirard, C.; Smets, M.; et al. Surgical Management of Endometriosis. Best Pract. Res. Clin. Obstet. Gynaecol. 2004, 18, 329–348. - Vallvé-Juanico, J.; Houshdaran, S.; Giudice, L.C. The Endometrial Immune Environment of Women with Endometriosis. Hum. Reprod. Update 2019, 25, 564–591. - Abramiuk, M.; Grywalska, E.; Małkowska, P.; et al. The Role of the Immune System in the Development of Endometriosis. Cells 2022, 11, 2028. - Ramírez-Pavez, T.N.; Martínez-Esparza, M.; Ruiz-Alcaraz, A.J.; et al. The Role of Peritoneal Macrophages in Endometriosis. Int. J. Mol. Sci. 2021, 22, 10792. - Kolanska, K.; Alijotas-Reig, J.; Cohen, J.; et al. Endometriosis with Infertility: A Comprehensive Review on the Role of Immune Deregulation and Immunomodulation Therapy. Am. J. Reprod. Immunol. 2021, 85, e13384. - Seli, E.; Arici, A. Endometriosis: Interaction of Immune and Endocrine Systems. Semin. Reprod. Med. 2003, 21, 135–144. - Steele, R.W.; Dmowski, W.P.; Marmer, D.J. Immunologic Aspects of Human Endometriosis. Am. J. Reprod. Immunol. 1984, 6, 33–36. - Podgaec, S.; Abrao, M.S.; Dias, J.A. Jr; et al. Endometriosis: An Inflammatory Disease with a Th2 Immune Response Component. Hum. Reprod. 2007, 22, 1373–1379. - Sobstyl, A.; Chałupnik, A.; Mertowska, P.; et al. How Do Microorganisms Influence the Development of Endometriosis? Participation of Genital, Intestinal and Oral Microbiota in Metabolic Regulation and Immunopathogenesis of Endometriosis. Int. J. Mol. Sci. 2023, 24, 10920. - Moghaddam, M.Z.; Ansariniya, H.; Seifati, S.M.; et al. Immunopathogenesis of Endometriosis: An Overview of the Role of Innate and Adaptive Immune Cells and Their Mediators. Am. J. Reprod. Immunol. 2022, 87, e13537. - Schulke, L.; Berbic, M.; Manconi, F.; et al. Dendritic Cell Populations in the Eutopic and Ectopic Endometrium of Women With Endometriosis. Hum. Reprod. 2009, 24, 1695–1703. - Capobianco, A.; Rovere-Querini, P. Endometriosis, a Disease of the Macrophage. Front. Immunol. 2013, 4, 9. - Tran, L.V.; Tokushige, N.; Berbic, M.; et al. Macrophages and Nerve Fibres in Peritoneal Endometriosis. Hum. Reprod. 2009, 24, 835–841. - Oral, E.; Olive, D.L.; Arici, A. The Peritoneal Environment in Endometriosis. Hum. Reprod. Update. 1996, 2, 385–398. - Young, V.J.; Brown, J.K.; Saunders, P.T.; et al. The Role of the Peritoneum in the Pathogenesis of Endometriosis. Hum. Reprod. Update. 2013, 19, 558–569. - Králíčková, M.; Fiala, L.; Losan, P.; et al. Altered Immunity in Endometriosis: What Came First? Immunol. Invest. 2018, 47, 569–582. - Guermonprez, P.; Valladeau, J.; Zitvogel, L.; et al. Antigen Presentation and T Cell Stimulation by Dendritic Cells. Annu. Rev. Immunol. 2002, 20, 621–667. - Savina, A.; Amigorena, S. Phagocytosis and Antigen Presentation in Dendritic Cells. Immunol. Rev. 2007, 219, 143–156. - Khan, K.N.; Kitajima, M.; Hiraki, K.; et al. Toll-Like Receptors in Innate Immunity: Role of Bacterial Endotoxin and Toll-Like Receptor 4 in Endometrium and Endometriosis. Gynecol. Obstet. Invest. 2009, 68, 40–52. - Griffiths, K.L.; O'Neill, H.C. Dendritic Cells as Immune Regulators: The Mouse Model. J. Cell. Mol. Med. 2008, 12, 1909–1914. - Drakes, M.; Blanchard, T.; Czinn, S. Bacterial Probiotic Modulation of Dendritic Cells. Infect. Immun. 2004, 72, 3299–3309. - Kang, Y.J.; Jeung, I.C.; Park, A.; et al. An Increased Level of IL-6 Suppresses NK Cell Activity in Peritoneal Fluid of Patients With Endometriosis via Regulation of SHP-2 Expression. Hum. Reprod. 2014, 29, 2176–2189. - Reis, J.L.; Rosa, N.N.; Ângelo-Dias, M.; et al. Natural Killer Cell Receptors and Endometriosis: A Systematic Review. Int. J. Mol. Sci. 2022, 24, 331. - Guo, S.W.; Du, Y.; Liu, X. Platelet-Derived TGF-β1 Mediates the Down-Modulation of NKG2D Expression and May Be Responsible for Impaired Natural Killer (NK) Cytotoxicity in Women With Endometriosis. Hum. Reprod. 2016, 31, 1462–1474. - Matsuoka, S.; Maeda, N.; Izumiya, C.; et al. Expression of Inhibitory-Motif Killer Immunoglobulin-Like Receptor, KIR2DL1, Is Increased in Natural Killer Cells From Women With Pelvic Endometriosis. Am. J. Reprod. Immunol. 2005, 53, 249–254. - Hoogstad-van Evert, J.; Paap, R.; Nap, A.; et al. The Promises of Natural Killer Cell Therapy in Endometriosis. Int. J. Mol. Sci. 2022, 23, 5539. - Igarashi, T.; Wynberg, J.; Srinivasan, R.; et al. Enhanced Cytotoxicity of Allogeneic NK Cells With Killer Immunoglobulin-Like Receptor Ligand Incompatibility Against Melanoma and Renal Cell Carcinoma Cells. Blood 2004, 104, 170–177. - Yu, J.; Venstrom, J.M.; Liu, X.R.; et al. Breaking Tolerance to Self, Circulating Natural Killer Cells Expressing Inhibitory KIR for Non-Self HLA Exhibit Effector Function After T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation. Blood 2009, 113, 3875–3884. - Hirata, T.; Osuga, Y.; Takamura, M.; et al. Recruitment of CCR6-Expressing Th17 Cells by CCL20 Secreted From IL-1β-, TNF-α-, and IL-17A-Stimulated Endometriotic Stromal Cells. Endocrinology 2010, 151, 5468–5476. - Mucida, D.; Park, Y.; Kim, G.; et al. Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid. Science 2007, 317, 256–260. - Kimura, A.; Kishimoto, T. IL-6: Regulator of Treg/Th17 Balance. Eur. J. Immunol. 2010, 40, 1830–1835. - Nishihara, M.; Ogura, H.; Ueda, N.; et al. IL-6-gp130-STAT3 in T Cells Directs the Development of IL-17+ Th With a Minimum Effect on That of Treg in the Steady State. Int. Immunol. 2007, 19, 695–702. - Chaudhry, A.; Rudra, D.; Treuting, P.; et al. CD4+ Regulatory T Cells Control TH17 Responses in a Stat3-Dependent Manner. Science 2009, 326, 986–991. - Dai, H.; Zheng, R.; Wang, L.; et al. ICS/LABA Combined With Subcutaneous Immunotherapy Modulates the Th17/Treg Imbalance in Asthmatic Children. Front. Immunol. 2022, 13, 779072. - Taylor, P.V.; Maloney, M.D.; Campbell, J.M.; et al. Autoreactivity in Women With Endometriosis. Br. J. Obstet. Gynaecol. 1991, 98, 680–684. - Barrier, B.F. Immunology of Endometriosis. Clin. Obstet. Gynecol. 2010, 53, 397–402. - Gorai, I.; Ishikawa, M.; Onose, R.; et al. Antiendometrial Autoantibodies Are Generated in Patients With Endometriosis. Am. J. Reprod. Immunol. 1993, 29, 116–123. - Ulukus, M.; Arici, A. Immunology of Endometriosis. Minerva Ginecol. 2005, 57, 237–248. - Hever, A.; Roth, R.B.; Hevezi, P.; et al. Human Endometriosis Is Associated With Plasma Cells and Overexpression of B Lymphocyte Stimulator. Proc. Natl. Acad. Sci. 2007, 104, 12451–12456. - Burbelo, P.D.; Iadarola, M.J.; Keller, J.M.; et al. Autoantibodies Targeting Intracellular and Extracellular Proteins in Autoimmunity. Front. Immunol. 2021, 12, 548469. - Suryawanshi, S.; Huang, X.; Elishaev, E.; et al. Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer. Clin. Cancer Res. 2014, 20, 6163–6174. - Fan, Y.Y.; Chen, H.Y.; Chen, W.; et al. Expression of Inflammatory Cytokines in Serum and Peritoneal Fluid from Patients with Different Stages of Endometriosis. Gynecol. Endocrinol. 2018, 34, 507–512. - Shi, J.L.; Zheng, Z.M.; Chen, M.; et al. IL-17: An Important Pathogenic Factor in Endometriosis. Int. J. Med. Sci. 2022, 19, 769–778. - Miller, J.E.; Ahn, S.H.; Marks, R.M.; et al. IL-17A Modulates Peritoneal Macrophage Recruitment and M2 Polarization in Endometriosis. Front. Immunol. 2020, 11, 108. - Nishimoto-Kakiuchi, A.; Sato, I.; Nakano, K.; et al. A Long-Acting Anti-IL-8 Antibody Improves Inflammation and Fibrosis in Endometriosis. Sci. Transl. Med. 2023, 15, eabq5858. - Uzuner, C.; Mak, J.; El-Assaad, F.; et al. The Bidirectional Relationship between Endometriosis and Microbiome. Front. Endocrinol. 2023, 14, 1110824. - Jiang, I.; Yong, P.J.; Allaire, C.; et al. Intricate Connections between the Microbiota and Endometriosis. Int. J. Mol. Sci. 2021, 22, 5644. - Leonardi, M.; Hicks, C.; El-Assaad, F.; et al. Endometriosis and the Microbiome: A Systematic Review. BJOG 2020, 127, 239–249. - Chadchan, S.B.; Popli, P.; Ambati, C.R.; et al. Gut Microbiota-Derived Short-Chain Fatty Acids Protect against the Progression of Endometriosis. Life Sci. Alliance 2021, 4, e202101224. - Salmeri, N.; Sinagra, E.; Dolci, C.; et al. Microbiota in Irritable Bowel Syndrome and Endometriosis: Birds of a Feather Flock Together—A Review. Microorganisms 2023, 11, 2089. - Li, W.; Lin, A.; Qi, L.; et al. Immunotherapy: A Promising Novel Endometriosis Therapy. Front. Immunol. 2023, 14, 1128301. - Maksym, R.B.; Hoffmann-Młodzianowska, M.; Skibińska, M.; et al. Immunology and Immunotherapy of Endometriosis. J. Clin. Med. 2021, 10, 5879. - Gazvani, R.; Templeton, A. Peritoneal Environment, Cytokines and Angiogenesis in the Pathophysiology of Endometriosis. Reproduction 2002, 123, 217–226. - Hirota, Y.; Osuga, Y.; Hirata, T.; et al. Activation of Protease-Activated Receptor 2 Stimulates Proliferation and Interleukin (IL)-6 and IL-8 Secretion of Endometriotic Stromal Cells. Hum. Reprod. 2005, 20, 3547–3553. - Gogacz, M.; Winkler, I.; Bojarska-Junak, A.; et al. Increased Percentage of Th17 Cells in Peritoneal Fluid Is Associated with Severity of Endometriosis. J. Reprod. Immunol. 2016, 117, 39–44.