Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives

Chen S, Siman Chen, Liu Y, Yukai Liu, Zhiqi Zhong, Zhong Z, Wei C, Chunyan Wei, Yuyin Liu, Zhu X, Xiao‐Yong Zhu, Xiaoyong Zhu
Frontiers in immunology · 2023 · vol. 14 , pp. 1134663 · doi:10.3389/fimmu.2023.1134663 · PMID:36865552 · PMC9971222 · W4320724174
review OA: gold CC0 ⤵ 83 in-corpus citations
📄 Open PDF Full text JSON View on OpenAlex View on PubMed View at publisher
⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This review explores how the peritoneal immune microenvironment, involving various immune cells and cytokines, contributes to endometriosis pathogenesis and discusses potential immune-regulating diagnostic biomarkers and therapies.

One-sentence paraphrase of the abstract; not a substitute for reading it. No clinical advice. How this works

⚙ AI-generated deep summary by claude@2026-06, 2026-06-09 · read from full text ⓘ

This review examines the peritoneal immune microenvironment in endometriosis, synthesizing evidence that innate and adaptive immune dysregulation after retrograde menstruation contributes to the implantation, vascularization, and fibrogenesis of ectopic endometrial lesions. It summarizes findings that peritoneal macrophages, NK cells, dendritic cells, neutrophils, T cells, and B cells—along with cytokines such as IL-1β, IL-6, IL-8, TNF-α, and TGF-β—shape a pro-inflammatory early environment that can shift toward immune tolerance, and discusses proposed mechanisms including reduced macrophage phagocytic ability, monocyte recruitment, and macrophage M1/M2 polarization (with noted conflicting views). The paper describes endocrine influences (estrogen overexpression and progesterone resistance) on immune function and outlines prospects for nonhormonal, immune microenvironment–targeted approaches and potential diagnostic biomarkers, while explicitly relying on the limitations of current hormonal therapy rather than providing new experimental data. This paper is centrally about endometriosis — it focuses on the role of the peritoneal immune microenvironment in endometriosis pathogenesis and therapeutic prospects.

Read from the paper's body, not the abstract. Not a substitute for reading the paper. No clinical advice. How this works

Abstract

Endometriosis, an estrogen-dependent chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, affects 10% of reproductive-age women. Although the pathogenesis of endometriosis is uncertain, it is widely accepted that retrograde menstruation results in ectopic endometrial tissue implantation. Given that not all women with retrograde menstruation develop endometriosis, immune factors have been hypothesized to affect the pathogenesis of endometriosis. In this review, we demonstrate that the peritoneal immune microenvironment, including innate immunity and adaptive immunity, plays a central role in the pathogenesis of endometriosis. Current evidence supports the fact that immune cells, such as macrophages, natural killer (NK) cells, dendritic cells (DCs), neutrophils, T cells, and B cells, as well as cytokines and inflammatory mediators, contribute to the vascularization and fibrogenesis of endometriotic lesions, accelerating the implantation and development of ectopic endometrial lesions. Endocrine system dysfunction influences the immune microenvironment through overexpressed estrogen and progesterone resistance. In light of the limitations of hormonal therapy, we describe the prospects for potential diagnostic biomarkers and nonhormonal therapy based on the regulation of the immune microenvironment. Further studies are warranted to explore the available diagnostic biomarkers and immunological therapeutic strategies for endometriosis.
Full text 58,843 characters · extracted from pmc-nxml · 4 sections · click to expand

The

From the above, it can be seen that the peritoneal immune environment plays a central role in the pathogenesis of endometriosis. The gold standard technique for the diagnosis of endometriosis remains laparoscopic visualization with histologic verification, and the main treatment methods are still surgery and hormonal therapy ( 1 ). There is an average initial diagnostic delay of 8-10 years, which worsens the prognosis, increases the risk of recurrence, and reduces the life quality of patients. New diagnostic biomarkers and therapeutic targets are urgently needed to improve the early diagnosis and treatment of endometriosis. Therefore, it is beneficial to regard immune mediators as diagnostic tools and regulate the immune environment to treat patients with endometriosis. There are a variety of potential biomarkers for the noninvasive diagnosis of endometriosis, including cytokines, inflammatory mediators, transcriptomics, genomics, proteomics, and metabolomics. However, none of them has been proven to be a sensitive and reliable diagnostic biomarker. Cytokines and inflammatory mediators such as IL-1, IL-6, IL-8, IL-12, IFN-γ, MCP-1, TNF-α, sTNFR-1, and CCL5 (RANTES), which are measured in the serum and PF of patients with endometriosis, have the potential to serve as diagnostic biomarkers in patients with endometriosis ( 23 , 159 ). Considering that the elevations in the levels of these mediators can be seen in multiple inflammatory diseases aside from endometriosis, the models of combined tests are more accurate and specific than those of a single test. Due to the increased concentrations of glycodelin-A in serum and PF, higher levels of IL-6 and IL-8 in the PF, and lower levels of leptin in the PF of patients with endometriosis, Kocbek V et al. proposed a few diagnostic models ( 160 ). For instance, the leptin/glycodelin-A ratio and ficolin 2/glycodelin-A ratio in serum, the biglycan/leptin ratio and RANTES/IL-6 ratio, and the ficolin2/glycodelin-A ratio accompanied by the concentration of IL-8 ( 160 ). Serum cancer antigen (CA)-125 can be a preoperative predictor of extensive endometriosis lesions, like severe adhesions and ruptured endometriotic cysts. The sensitivity and specificity of the diagnosis can be improved through combined testing with other molecules ( 159 ). Moreover, it is reported that the neutrophil-to-lymphocyte ratio (NLR) adjuvant to serum CA-125 is regarded as a potential diagnostic tool correlated with the severity of endometriosis ( 161 ). In contrast, Kim argued that the NLR and serum CA-125 levels were not associated with the severity of endometriosis ( 162 ). The combined test of CCR1 mRNA, MCP-1, and CA-125 in serum has been proven efficient for the diagnosis or exclusion of endometriosis, with 92.2% sensitivity and 81.6% specificity ( 163 ). Macrophages play essential roles in the etiology of endometriosis. A previous study revealed that five genes associated with M2 macrophages have a potential diagnostic value with the help of the CIBERSORT and WGCNA algorithms. For instance, the expression of bridging integrator 2 (BIN2), CCR5, and macrophage mannose receptor1 (MRC1) increased, and the expression of spleen tyrosine kinase (SYK) and metalloproteinase 12 (ADAM12) decreased in endometriosis tissues compared to non-endometriosis tissues ( 164 ). However, more studies are warranted to identify these five genes that could be used as diagnostic biomarkers in clinical settings. A case-control study demonstrated that the macrophage migration inhibitory factor (MIF) protein level was significantly higher in patients with endometriosis compared to those in the control group, and this biomarker was associated with the severity of endometriosis. According to this study, MIF may be a potential serum biomarker to be used in the diagnosis of endometriosis and the detection of its severity ( 165 ). Furthermore, the concentration of VEGF-A, a kind of angiogenic growth factor secreted by macrophages and other cells, decreased after the surgical excision of endometriosis lesions. Mohamed ML et al. proved that the measurement of VEGF-A titers in peripheral blood is more effective than the measurement of CA-125 titers in diagnosing advanced endometriosis (at a cut-off of 680 pg/ml) after surgery ( 166 ). A recent study proposed that active-screen plasma nitriding (ASPN) can be used as a diagnostic biomarker and a potential therapeutic target in endometriosis, which is negatively correlated with the percentage of cytotoxic lymphocytes and NK cells and positively correlated with the percentage of T cells, B cells, fibroblasts, and endothelial cells by the Least Absolute Shrinkage and Selection Operator (LASSO) regression and generalized linear models (GLMs) from the GSE141549 datasets ( 167 ). Notably, TLR-2, which is essential in the innate immune system, was upregulated in the myeloid dendritic cells and B cells in patients with endometriosis. TLR-2 has been proposed as a potential noninvasive biomarker ( 168 ). There are many immunotherapy targeting macrophages to regulate the peritoneal immune microenvironment in endometriosis. Since macrophage depletion by intraperitoneal injection of liposomal alendronate inhibited the growth of endometriosis lesions, macrophage depletion in humans might be a potential treatment for endometriosis patients ( 169 ). CD47-SIRP-α) is considered a macrophage-associated immune checkpoint, and the expression of CD47 is increased in the peritoneal cavities of patients with endometriosis. Li et al. demonstrated that targeting CD47 could increase the phagocytic capacity of macrophages by blocking the CD47-SIRP-α pathway, which inhibits the development of endometriosis ( 170 ). Besides, Cui et al. identified 23 small molecules related to macrophages that promote endometriosis progression as potential treatment targets from the cMAP database. The top three small molecules, Celastrol, MS-275, and dexverapami, which have high absolute enrichment values, are selected as potential therapeutic agents. With anti-tumor and anti-inflammatory activity, these target molecules could be helpful in the management of tumors and endometriosis ( 164 ). Given that ROS produced by macrophages promote endometriosis, antioxidants may be used to suppress oxidative stress and endometriosis ( 171 ). Vitamin C, a water-soluble antioxidant, has been proven to reduce endometriotic cyst volume and weight in mouse models ( 172 ). Some human clinical studies have demonstrated that vitamins C and E inhibit oxidative stress and decrease chronic pelvic pain and dysmenorrhea in patients with endometriosis ( 173 , 174 ). Curcumin, an antioxidant and anti-inflammatory agent, can reduce the expression of ROS and NO to suppress oxidative stress and inhibit the NF-κB pathway and the expression of TNF-α, IL-1, IL-6, and IL-8 in macrophages of mouse models; thus, it has a potential therapeutic effect on endometriosis ( 175 ). Other antioxidants like Melatonin and N-acetyl-l-cysteine (NAC) also positively suppress oxidative stress and relieve endometriosis-related pain ( 176 – 178 ). VEGF, which is produced by macrophages and other immune cells promotes angiogenesis and induces endometrial tissue attachment and implantation. Resveratrol has been proven to suppress the expression of VEGF in the PF and reduce endometriotic lesion volume in animal models, both in vivo and in vitro ( 179 ). Laschke MW reported that Epigallocatechin-3-gallate (EGCG), the major component of green tea, inhibited the development of endometriotic lesions by suppressing the proliferation and VEGF expression of endometrial cells as well as angiogenesis and blood perfusion ( 180 ). Liu Y et al. established a mouse model and found that Crocin inhibited inflammation, angiogenesis, and the growth of endometriosis lesions through decreased expression of VEGF, proliferating cell nuclear antigen (PCNA), and inflammatory cytokines in the lesions ( 181 ). Considering that NK cells participated in the pathogenesis of endometriosis due to decreased toxicity, the activation of these cells could be a strategy to treat endometriosis. An experiment involving the intraperitoneal injection of Lactobacillus gasseri OLL2809 (a probiotic lactobacillus that stimulates IL-12 production) for 21 days resulted in the activation of NK cells toxicity and a reduction in the number of ectopic endometriotic lesions in mouse models. They also conducted a randomized, double-blind, placebo-controlled study and showed that L. gasseri OLL2809 could relieve endometriosis-associated pain ( 182 ). On the other hand, due to the upregulated expression of the inhibitory receptors observed in endometriosis, the inhibition of KIR2DL1, LILRB1/2, and NKG2A by monoclonal antibodies may have therapeutic effects on endometriosis ( 183 ). Moreover, the reduction of TGF-β levels could be another potential treatment option ( 183 ). Besides, stimulating NK cells with intraperitoneal injections of IL-2 has been proven to decrease endometriosis lesion sizes in the rat model ( 184 ). Although there is no available evidence in humans, it is a potential treatment option for endometriosis. Notably, the Bacillus Calmette–Guérin (BCG) tuberculosis vaccine, which has been proven to recruit NK cells, increase cytotoxicity, and reduce ectopic endometrial lesions in animal models, has been proposed as a treatment option ( 185 ). Considering the increased expression of ER in ESCs and macrophages, we can explore drugs that regulate ER levels. In a baboon model of endometriosis, simvastatin has been proven to inhibit the growth of endometrial lesions by downregulating the expression of ER-β and upregulating the expression of ER-α via the inhibition of the mevalonate pathway ( 186 ). Another study reported that oleuropein, a natural product, selectively inhibited ER-β, suppressing the growth of endometriotic lesions by inhibiting the proliferation and activating the apoptosis of ESCs and improving fertility by partly recovering the impaired decidualization in mouse models ( 187 ).

Intro

Endometriosis, a chronic inflammatory disease, is defined as the growth of endometrium-like tissues outside the uterine cavity, at locations such as the peritoneum, ovary, and cervix. The typical clinical symptoms of endometriosis are progressive dysmenorrhea, chronic pelvic pain, deep dyspareunia, and infertility, all of which affect the patient’s quality of life ( 1 ). It is estimated that 10% of reproductive-age women are affected by endometriosis ( 2 ). Although the etiology and pathogenesis of endometriosis remain indistinct, the retrograde menstruation theory proposed by Sampson in 1921 is widely accepted. Besides, there are other hypotheses of the pathophysiology of endometriosis, including coelomic metaplasia and vascular and lymphatic metastasis ( 3 ). However, none of them were able to adequately explain all pathological types of endometriosis. Additionally, it is generally accepted that immune, endocrine, genetic, and environmental factors are also involved in the pathogenesis of endometriosis ( 4 ). Retrograde menstruation refers to the reflux of menstrual debris containing endometrial cells through the fallopian tubes into the peritoneal cavity, where they are implanted in the peritoneum and pelvic organs ( 5 ). Some studies suggest that not all women with retrograde menstruation develop endometriosis and those with innate or adaptive immune disorders are more likely to have it ( 6 ). After menstrual debris flows into the abdominal cavity, the innate and adaptive immune systems are activated and try to clear the fragments. The immune cells infiltrate and begin to repair the peritoneal cavity. As time passes, persistent endometrial debris may lead to immune system overload, contributing to immune dysfunction ( 7 ). Immune microenvironment dysfunction improves the adhesion, proliferation, and invasion of the endometrial cells, contributing to the pathogenesis of endometriosis. Moreover, cytokines in the peritoneal fluid (PF) can directly stimulate the proliferation and invasion of endometrial cells and neovascularization, accelerating the progression of endometriotic lesions ( 8 ). The endocrine system plays a central role in the pathogenesis of endometriosis. Estrogen overexpression and progesterone resistance lead to immune system dysfunction and affect the immune microenvironment of the peritoneal cavity. In addition to surgical treatment, the current medical treatment for endometriosis is hormonal therapy. In light of the side effects and relatively poor efficacy of hormonal therapy, new nonhormonal treatments such as immunotherapy are urgently required. Targeted immunotherapy aimed at regulating the immune microenvironment for cancer has made great progress in recent years ( 9 ). Immunotherapeutic targets are comprised of specific genetic mutations, clusters of differentiation molecules, and immune checkpoint molecules on immune cells, such as CD25, CTLA-4, and programmed death-1 (PD-1) ( 10 – 12 ). Adoptive cell immunotherapy, including the chimeric antigen receptor (CAR)-T cell and the engineered T-cell receptor (TCR)-T cell, has been developed to boost the anticancer immune microenvironment ( 13 ). Consequently, immunotherapy for endometriosis has great potential to provide more specific and effective therapeutic alternatives with fewer side effects. In this article, we discuss the role of the peritoneal immune microenvironment in the pathogenesis of endometriosis and provide future perspectives on nonhormonal treatment based on the regulation of the immune microenvironment.

Discussion

Endometriosis, a chronic inflammatory disease characterized by the implantation of endometrium-like tissues outside the uterine cavity, affects approximately 10% of reproductive-age women. Considering that the retrograde menstruation theory could not explain the fact that not all women with retrograde menstruation have endometriosis, we discussed the immune factors involved in the peritoneal immune microenvironment of endometriosis in this review. In healthy women without endometriosis, immune cells, such as macrophages and NK cells, are recruited and activated, after which they eliminate debris after the reflux of endometrial tissues into the peritoneal cavity. Besides, chemokines secreted by immune cells contribute to a pro-inflammatory environment by inhibiting the implantation of ectopic endometrial lesions. As a result, the abnormal peritoneal immune environment plays an essential role in the pathogenesis of endometriosis. The innate immune system participates in the pathogenesis of endometriosis. Macrophages in the PF of patients with endometriosis have decreased phagocytotic ability and produce inflammatory cytokines and angiogenesis factors, contributing to ectopic cell survival, vascularization, and fibrogenesis of endometriotic lesions, which accelerate the implantation and development of ectopic lesions. Recent studies have shown that the interaction between macrophages and nerves promotes the pathophysiology of endometriotic events. The reduction in the numbers and cytotoxicity of NK cells in the PF of endometriosis patients caused by the increased expression of inhibitory receptors, such as NKG2A, KIR2DL1 and LILRB1/2, immune checkpoint PD-1/PD-L1, TGF-β, IL-6, and IL-10, contribute to immune escape and ectopic endometrial tissue implantation. Dendritic cells are also involved in the promotion of angiogenesis and lesion formation in endometriosis. In addition, neutrophils are recruited early and secrete VEGF and NETs; thus, they play a crucial role in the initial formation and angiogenesis of endometriosis lesions. There are other components of innate immunity, including TNF-α, IL-1β, IL-6, IL-17A, ICAM-1/LFA-1, and HMGB-1, that participate in the pathogenesis of endometriosis. On the other hand, the adaptive immune system also plays a crucial role in the pathogenesis of endometriosis. T lymphocytes mediated cellular immunity is involved in endometriosis pathophysiology, which stimulates the generation of Treg cells while inhibiting the generation of Th17 cells, contributing to immunosuppression and ESCs proliferation and invasion. The anti-endometrial antibodies and chemokines secreted by B cells, such as IL-6, IL-17, and IFN-γ, also participate in the pathogenesis of endometriosis. Endometriosis is an estrogen-dependent chronic inflammatory disease in whose pathogenesis endocrine-immunological interactions play an indispensable role. Estrogen overexpression and progesterone resistance result in peritoneal immune microenvironment dysfunction. The enhanced expression of ER-α and ER-β induces macrophage recruitment and M2 polarization, and decreases the phagocytic capacity and expression of pro-inflammatory cytokines, inhibiting the inflammatory response. Estrogen inhibits the cytotoxic activity of NK cells on account of low autophagy of ESCs, promoting the immune escape of ESCs and the development of endometrial lesions. Hormones also play an essential role in affecting the activity of neutrophils, T cells, and Bells. They also affect the expression of pro-inflammatory cytokines. Hormonal therapy, including combined oral contraceptives, progestogens, antiprogestogens, GnRHa, and aromatase inhibitors, is the commonly prescribed pharmacological treatment ( 188 ). Although these drugs could lead to significant pain relief, the recurrence of pain after discontinuing the medication and side effects are essential issues for these treatments. Due to its impact on suppressing ovulation and inducing amenorrhea via the regulation of the endocrine system, it is unavailable for patients with fertility intentions. Furthermore, some hormone medications, such as progestogens and GnRHa, would produce side effects, such as cardiovascular risks, amenorrhea, hot flashes, bone mineral density decline, and vulvovaginal atrophy, all of which negatively affect the patient’s quality of life ( 188 ). Immunotherapy, which could improve the peritoneal immune microenvironment and inhibit the development of endometriosis lesions, works in synergy with hormonal therapy to fundamentally relieve troubling symptoms of patients with fewer endocrine effects. To ensure treatment efficiency and decrease side effects, we provide future perspectives for potential diagnostic biomarkers and nonhormonal therapy based on the regulation of the immune microenvironment. Further studies are urgently needed to comprehensively understand the immune pathophysiological mechanisms of endometriosis and explore the available diagnostic biomarkers and optimal immunological therapeutic strategies targeting endometriosis to alleviate pain, improve fertility, and enhance patients’ quality of life.

Author Contributions

SC searched the literature, generated the figures, and prepared the manuscript. YuL searched the literature and revised this manuscript. ZZ, CW, YL participated in the design of this research. XZ initiated and supervised the study and edited the manuscript. All authors contributed to the article and approved the submitted version.

Text is read by the "Ask this paper" AI Q&A widget below. Extraction quality varies by source — PMC NXML preserves structure cleanly, OA-HTML may include some navigation residue, and OA-PDF can have broken hyphenation. The publisher copy (via DOI) is the canonical version.

My notes (saved in your browser only)

⚙ Ask this paper AI returns verbatim quotes from the full text · source: pmc-nxml ⓘ

Answers must be backed by verbatim quotes from this paper's full text. Hallucinated quotes are dropped automatically; if no verbatim passage answers the question, we say so. How this works

Condition tags

endometriosis

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

References (100)

Cited by (50)

Source provenance

europepmc
last seen: 2026-07-29T06:27:48.050232+00:00
openalex
last seen: 2026-06-10T17:14:06.276822+00:00
pubmed
last seen: 2026-07-29T06:26:59.293942+00:00
License: CC0 · commercial use OK