Immunotherapy: A promising novel endometriosis therapy

The paper reviews endometriosis, a benign yet invasive gynecologic condition associated with pelvic pain and infertility, whose precise pathogenesis remains unclear. The authors emphasize genetic susceptibility (e.g., twin studies, GWAS) and the widely accepted retrograde menstruation theory that triggers local immune responses and fibrosis upon ectopic implantation. They highlight the central role of immune dysregulation—particularly involving neutrophils, macrophages, NK cells, T-cell subsets, mast cells, and dendritic cells—in enabling survival, implantation, angiogenesis, and growth of ectopic endometrial tissue. The purpose is to synthesize evidence that immune dysfunction contributes to disease initiation and progression and to evaluate immunotherapeutic strategies that target immune cells, cytokines, and signaling pathways as potential treatments beyond surgery and hormonal therapy.

The review synthesizes evidence on immune cell involvement in endometriosis pathogenesis: (1) Neutrophils are elevated in peritoneal fluid, driven by chemokines (IL-8, ENA-78, HNP1-3), and their depletion reduces lesion formation in mice; they likely contribute to pelvic pain. (2) Macrophages are increased and contribute via proinflammatory cytokine secretion (TNF, IL-6, IL-1β), promotion of endometrial stromal cell proliferation, and VEGF-mediated angiogenesis; alternatively activated (M2) macrophages are implicated; exosomes from lesions drive M2 polarization and reduce phagocytosis; CD47 overexpression on ectopic cells sends a “don’t eat me” signal. (3) NK cells exhibit reduced cytotoxicity (notably CD56dimCD16+ subset) in blood and peritoneal fluid, influenced by cytokines (TGF-β, IL-6, IL-15), facilitating immune escape. (4) T cells: TH2, TH17, and Tregs are increased; IL-4, TSLP, and IL-17A promote inflammation and proliferation; Tregs increase local immunosuppression and are linked to infertility and pain. (5) Mast cells are increased and activated in lesions, clustering around vessels and stroma; elevated SCF suggests enhanced recruitment/differentiation. (6) Dendritic cells are increased; plasmacytoid DC-derived IL-10 promotes angiogenesis; increased immature DCs reduce antigen presentation, aiding immune escape. The review also compiles preclinical and limited clinical evidence on immunomodulatory therapies: immune cell modulators (CD47 blockade, exosome-targeting, NK activation via probiotics and Helixor A, PD-1 pathway inhibition, mast cell stabilizers/inhibitors, loratadine), cytokine modulators (anti-TNF agents, IL-12 and IL-37 administration, anti–TGF-β approaches), NF-κB inhibitors, interferons, danazol’s immunosuppressive effects, complement inhibitors (C3 and C1q targeting), COX-2 inhibitors, statins, mesenchymal stem cells, vitamin D, and BCG vaccination.

This is a narrative review. The authors identified and analyzed references (Medline cited in author contributions) spanning mechanistic, animal, and limited clinical studies on immunologic factors and immunotherapies in endometriosis. No formal systematic review methods (e.g., predefined inclusion criteria, risk-of-bias assessment, meta-analysis) are reported.

- Immune dysregulation is central to endometriosis pathogenesis: elevated neutrophils and macrophages with proinflammatory cytokines (TNF, IL-6, IL-1β), reduced NK cytotoxicity influenced by TGF-β, IL-6, IL-15, skewed T-cell subsets (TH2, TH17, Tregs), increased mast cells and immature dendritic cells. - Immune cell–targeted strategies: - CD47 blockade (siRNA or neutralizing antibodies) restores macrophage phagocytosis; CD47 is upregulated in ectopic tissue. - Anti-exosome approaches shift macrophage polarization away from M2, enhance phagocytosis, and reduce lesion development in mice. - NK activation via oral probiotics (Lactobacillus gasseri OLL2809) reduces lesions in mice; Helixor A increases NK cytotoxicity and inhibits lesion development. - PD-1 upregulation on T cells induced by endometriosis MSC signaling suggests PD-1 inhibition as a therapeutic avenue. - Mast cell stabilizers and inhibitors (e.g., palmitoyl ethanolamide, LNG-IUS under clinical evaluation; zafirlukast, sodium cromoglycate, JAK2 inhibitor tyrphostin preclinical) target elevated/activated mast cells. - Loratadine modulates macrophages, T cells, NK cytotoxicity, and B-cell proliferation; targets include IL-1α, TNF, TNF-β, IL-6, IFN-α/γ. - Cytokine and pathway modulators: - Anti-TNF agents (pentoxifylline, leflunomide, etanercept, infliximab, r-hTBP-1) show preclinical efficacy; etanercept blocks peritoneal fluid–driven endometrial proliferation; r-hTBP-1 inhibits lesion development in rat and baboon models. - Interleukins: IL-12 injections inhibit lesion development and enhance NK cytotoxicity in mice; rhIL-37 inhibits lesions by reducing IL-4 in DCs, shifting Th1/Th2 ratio, and promoting DC maturation via STAT3 inhibition. - TGF-β1 is elevated in lesions/peritoneal fluid; targeting TGF-β is posited to restore immune function and reduce ectopic cell survival/attachment/invasion. - NF-κB regulates inflammatory responses in ectopic stromal cells; inhibitors are proposed as candidates. - Other immunomodulators: - Interferons: recombinant IFN-α2b reduces intraperitoneal lesion area in rodents. - Danazol suppresses T-cell proliferation and monocyte IL-1/TNF production; reduces macrophage/monocyte cytotoxicity in mild disease. - Complement: C3 inhibition may block inflammatory cascades and restore NK cytotoxicity; C1q blockade may prevent M2 polarization and angiogenesis. - COX-2 inhibitors (e.g., celecoxib, glycyrrhizin, puerarin) reduce microvessel density, macrophage numbers, and VEGF/Flk-1 expression in lesions (preclinical); no clinical application data to date. - Statins (atorvastatin) reduce inflammatory gene expression, exhibit antiangiogenic/antioxidant effects; inhibit MCP-1 expression in implants. - Mesenchymal stem cells modulate cytokines (↓IL-1β, TNF; ↑IL-6, IL-8) and may downregulate chronic inflammation. - Vitamin D and derivatives show immunomodulatory effects; in a rat model, vitamin D3 reduced endometriotic cyst cross-sectional area by 48.8% and modulated cytokine production and Th1/Th2 balance via NF-κB downregulation of IL-12. - BCG vaccination reduces implant number in animal models, enhances NK cytotoxicity, promotes M1 macrophage polarization, and reduces IL-10 from M2 macrophages. - Evidence status summarized: numerous preclinical studies; limited clinical evidence includes LNG-IUS and danazol; clinical data on anti-TNF in nonhuman primates; overall, clinical translation remains limited.

The compiled evidence supports the hypothesis that endometriosis is driven in part by immune dysfunction that allows ectopic endometrial cells to survive, implant, and promote angiogenesis and fibrosis. By targeting specific immune cells (macrophages, NK, T cells, mast cells, DCs) and inflammatory pathways (TNF, ILs, TGF-β, NF-κB, complement, COX-2), immunotherapies can reduce lesion establishment and growth in preclinical models and modulate the peritoneal immune environment toward restoring surveillance and cytotoxicity. These findings extend treatment strategies beyond surgery and hormonal suppression, addressing underlying immune pathophysiology. However, while animal and in vitro data are encouraging, human clinical evidence remains sparse. Translational challenges include validating efficacy and safety, optimizing delivery and dosing, and identifying patient subgroups most likely to benefit (e.g., those with pronounced NK dysfunction or macrophage M2 polarization). The review underscores the potential of combination approaches (e.g., hormonal plus immune modulation) and the need for biomarkers to monitor immune response and disease activity.

Immunotherapy is a promising avenue for endometriosis treatment, grounded in strong preclinical evidence that correcting immune dysregulation—enhancing macrophage phagocytosis and NK cytotoxicity, rebalancing T-cell subsets, stabilizing mast cells, and modulating key cytokine and signaling pathways—can inhibit lesion development and progression. While traditional surgery and hormonal therapy remain mainstays with notable recurrence, immunomodulatory strategies offer mechanistic, potentially disease-modifying benefits. Future work should focus on elucidating detailed mechanisms of action, identifying predictive biomarkers, and conducting large-scale, multicenter clinical trials to establish efficacy and safety across diverse patient populations. Combination therapies and precision immunomodulation tailored to immune phenotypes warrant exploration.

- The review is narrative without a described systematic methodology, leaving potential selection bias in cited studies. - Most evidence is preclinical (in vitro, rodent, and limited nonhuman primate models), with scarce human clinical trial data. - Heterogeneity in models, dosing, and endpoints limits cross-study comparability and generalizability. - Exact mechanisms for several interventions (e.g., anti–TGF-β, NF-κB inhibitors, complement inhibitors) in human endometriosis remain to be fully delineated. - Safety, long-term outcomes, and fertility impacts of many immunotherapies are not established in humans.