Alterations in Cellular Immunity in Patients With Endometriosis: Systematic Review and Meta-Analysis

Determining the pathogenesis of endometriosis remains a major challenge in contemporary gynecology, and the investigation of alterations in cellular immunity may provide important insights into this issue. A comprehensive search of electronic databases (PubMed, The Cochrane Library, ClinicalTrials.gov, Scopus, Embase, and Google Scholar) identified 24 studies meeting the inclusion criteria for qualitative synthesis. The primary analysis compared the concentration of IL‐4 in peripheral blood (MD = 1.32, 95% CI: −15.00 to 17.63, p = 0.87); the secondary compared the concentration of HLA‐DR+‐macrophages (MD = −2.62, 95% CI: −8.98 to 3.73, p = 0.42) and HLA‐ABC+‐macrophages (MD = −6.84, 95% CI: −23.94 to 10.26, p = 0.43) in peritoneal fluid; the third compared the IL‐6 concentration in peritoneal fluid (MD = 338.00, 95% CI: 85.02 to 590.98, p = 0.009); the fourth compared the NK‐cell level in peritoneal fluid (MD = 6.75, 95% CI: −12.42 to 25.91, p = 0.49); the fifth compared the level of NK‐cells in ectopic and eutopic endometrium (MD = −9.12, 95% CI: −24.39 to 6.15, p = 0.24) between endometriosis and control groups. Overall, the included studies suggest that signaling pathways involving T lymphocytes, monocytes, macrophages, and natural killer cells are altered in patients with endometriosis.

cellular immunity, endometriosis, macrophages, natural killer cells, T‐lymphocytes 1. Introduction

The purpose of this systematic review and meta‐analysis was to assess changes in cellular immunity in patients with endometriosis. Endometriosis is a gynecological disease characterized by the presence of endometrial‐like tissue outside the uterine cavity [1]. It affects approximately 10% of women of reproductive age globally [2]. This estrogen‐dependent disorder is associated with a wide range of clinical manifestations, including chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and other symptoms that substantially impair quality of life and reproductive outcomes [3]. One of the major challenges in contemporary gynecology is to clarify the mechanisms underlying this disease in order to develop effective noninvasive diagnostic tools as well as surgical, pharmacological, and rehabilitative treatment strategies [4, 5]. Currently, the most widely accepted explanation for the formation of endometrial lesions is Sampson's theory of retrograde menstruation [6]. Nevertheless, this hypothesis remains controversial, as retrograde menstruation is a common phenomenon among many women, yet it does not always result in the development of endometriosis [7]. Moreover, this theory does not explain the occurrence of lesions outside the peritoneal cavity, such as those associated with uterine anomalies [8], or previously reported cases of fetal endometriosis identified in 25‐week‐old female fetuses [9]. Ongoing research has led to several additional hypotheses regarding the origin of endometriosis, including lymphatic and vascular spread, coelomic metaplasia, stem cell recruitment, and embryogenetic theories [10]. Another interesting hypothesis concerns disturbed iron metabolism: iron overload may induce oxidative stress and resistance to ferroptosis, thereby promoting the progression of endometriosis [11]. In‐depth studies have also shown that immune dysregulation is involved in endometriosis, as reflected by abnormal signaling pathways and altered cytokine secretion [12]. It has been proposed that ectopic endometrial‐like cells within the peritoneal cavity trigger an immune response that leads to hyperactivation of immune mechanisms [13]. This excessive immune activity results in persistent inflammation, increased cytokine production, and reduced cytotoxic function of peritoneal macrophages, which together may facilitate the progression of endometriotic lesions [14, 15]. Because the etiology and pathogenesis of endometriosis remain unclear, and noninvasive diagnosis remains challenging, we focused on immune dysregulation as a potential contributing factor, particularly alterations in cellular immunity. Dysfunction of key immune cells involved in maintaining peritoneal homeostasis may allow ectopic endometrial cells to survive and lesions to progress [16]. Therefore, the aim of this systematic review and meta‐analysis was to investigate alterations in T lymphocytes, natural killer cells, monocytes, macrophages, and neutrophils, as well as cytokines secreted by these cells, in order to assess changes in cellular immunity in different biological fluids of patients with endometriosis. 2. Methods 2.1. Study Design This systematic review was registered in the PROSPERO international prospective register of systematic reviews of the National Institute for Health Research (NIHR). The protocol registration number was CRD42024520072. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses 2020 (PRISMA) guidelines for reporting systematic reviews. Institutional Review Board (IRB) approval was not requested since the present study is a review [17]. 2.2. Data Sources An electronic search was conducted in PubMed, The Cochrane Library, ClinicalTrials.gov, Scopus, Embase, and Google Scholar. The authors used the following search terms: “endometriosis” and “cellular immunity.” The date of the last search was July 20, 2025.в To identify all potentially relevant studies, no restrictions or search filters were applied with regard to publication status, article type, or language. The search strategy in PubMed and The Cochrane Library was based on an advanced search builder, using the following keywords: (endometriosis) AND (cellular immunity), with no filters or limits applied. The search was also performed in ClinicalTrials.gov using the following advanced search terms: Endometriosis | Other terms: Cellular immunity. In addition, MeSH terms were used in PubMed (“Endometriosis”[Mesh]) AND (“Immunity, Cellular”[Mesh]) and in The Cochrane Library (MeSH descriptor: [Endometriosis] explode all trees and with qualifier(s): [immunology—IM]). 2.3. Study Selection The search was performed independently by three investigators (S.B., K.K., and K.M.). The search results were imported into a reference manager (Zotero, version 6.0.8). After the search, all records were screened by title and abstract. Non‐randomized clinical trials were selected, and full texts of all potentially relevant studies were assessed independently by the authors for eligibility. In addition, the reference lists of the retrieved articles were manually searched to identify additional relevant studies. Any disagreements regarding the inclusion or exclusion of studies, as well as any other discrepancies during the review process, were resolved by consultation with the fourth author (L.P.). 2.4. Eligibility Criteria and Main Outcomes The inclusion criteria for this systematic review were randomized and non‐randomized clinical trials evaluating changes in cellular immunity in patients with endometriosis. Only studies published in English were included. Case reports, preclinical studies, review articles, opinion articles, and studies published in abstract form were excluded because of their high risk of bias. Proceedings of scientific meetings and abstracts were also excluded. The primary outcome was the concentration of the main biomarkers of cellular immunity in blood, peritoneal fluid, or tissue samples from patients. 2.5. Quality Assessment Risk of bias was assessed for each included study using the Cochrane Handbook for Systematic Reviews of Interventions and the Cochrane Collaboration tools [18]. Three review authors (S.B., K.K., and K.M.) independently evaluated the quality of the selected studies. Any discrepancies between the reviewers were resolved by discussion or consultation with the fourth author (L.P.). Following the Cochrane Handbook for Systematic Reviews of Interventions, ROBINS‐I was used for non‐randomized studies, including prospective controlled studies, prospective cohort studies, retrospective studies, and other study designs [19]. These tools were also used to assess the risk of bias arising from reporting biases due to missing synthesis results. The visualization tool was created using the ROBVIS application [20]. 2.6. Statistical Analysis For quantitative synthesis, meta‐analysis was performed using RevMan 5.4, as recommended by the Cochrane Collaboration. Meta‐analyses of dichotomous outcomes were performed using the inverse variance method and a random‐effects model, because clinical and methodological heterogeneity among the included trials was expected. Results were reported as risk ratios (RRs) with 95% confidence intervals (CIs). Meta‐analyses of continuous outcomes were reported as mean differences (MDs) with 95% CIs. According to the Cochrane Handbook for Systematic Reviews of Interventions, an I2 value of 0 indicates no observed heterogeneity; values from 30% to 60% may represent moderate heterogeneity; values from 50% to 90% may represent substantial heterogeneity; and values from 75% to 100% indicate considerable heterogeneity. 3. Results The whole search strategy with the results is presented in the PRISMA flow diagram (Figure 1). The initial search produced 166 articles. After the MeSH search, 121 reports were identified: 109 from PubMed and 12 from the Cochrane Library. After removing duplicates and searching for the title and abstract of the articles, 204 publications were selected. Therefore, 40 reports were left for full‐text screening and analysis following our inclusion criteria. Twenty‐two articles did not meet the inclusion criteria for the reasons shown in Figure 1 and were excluded. Of these two studies were eliminated due to ineligible design, two—to ineligible inclusion criteria, eleven articles assessed another outcomes and three publications were not in English. Additionally, 752 articles were found in the references of the 24 articles included in the qualitative analyses. 16 of them were assessed for eligibility. Of these six studies were eliminated due to ineligible design, two due to ineligible inclusion criteria and six articles assessed another outcomes. The list of excluded studies is given in the Table S1. Two of these 16 publications were included in this systematic review. Eventually, 24 studies were retained for the qualitative synthesis. The characteristics of the included studies are provided in Table 1. TABLE 1. | № | Study (first author, year) | Intervention group (n) | Control group (n) | Outcomes measured | Results | |---|---|---|---|---|---| | 1 | Le et al. [22] | Women with laparoscopically and histologically confirmed endometriosis (n = 20) r‐ASRM stages: n = 5 – I; n = 3 – II; n = 4 – III; n = 8 – IV. Menstrual phase: not reported | Women without endometriosis (n = 9) Menstrual phase: not reported | Concentration of iTregs in peripheral blood Concentration of Th17 in peripheral blood Treg/Th17 ratio in peripheral blood | A statistically significant reduction of iTregs concentration in endometriosis group (p < 0.05). A statistically significant increase of Th17 concentration in endometriosis group (p < 0.05). A statistically significant reduction of Treg/Th17 ratio in endometriosis group (p < 0.05). | | 2 | Kusume et al. [38] | Women with laparoscopically and histologically confirmed endometriosis (n = 38) r‐ASRM stages: n = 9 – I; n = 3 – II; n = 8 – III; n = 18 – IV. Menstrual phase: n = 16 ‐ follicular; n = 22 ‐ luteal | Women without endometriosis (n = 59) Menstrual phase: n = 23 ‐ follicular; n = 36 ‐ luteal | Concentration of HLA‐ABC macrophages in peritoneal fluid Concentration of HLA‐DR macrophages in peritoneal fluid | endometriosis group vs control group −99.9 ± 0.4 vs 99.6 ± 1.2 (p < 0.05) endometriosis group vs control group −84.3 ± 12.7 vs 91.1 ± 10.2 (p < 0.05) | | 3 | Ho et al. [27] | Women with laparoscopically and histologically confirmed endometriosis (n = 51) r‐ASRM stages: n = 21 – I/II; n = 30 – III/IV. Menstrual phase: early follicular | Women without endometriosis (n = 19) Menstrual phase: early follicular | Concentration of NK in peritoneal fluid Concentration of HLA‐DR+CD4+CD3+ in peritoneal fluid Concentration of HLA‐DR+CD8+CD3+ in peritoneal fluid Concentration of CD25+CD4+CD3 + in peritoneal fluid Concentration of CD25+CD8+CD3 in peritoneal fluid Concentration of IFN‐γ (T‐h1) in peritoneal fluid Concentration of IL‐4 in peripheral blood Concentration of IL‐4 in peritoneal fluid Concentration of IL‐5 in peripheral blood Concentration of IL‐5 in peritoneal fluid | I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 21.7 ± 14.8 vs 17.1 ± 10.3 vs 13.8 ± 6.1 (p < 0.0002) I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 15.7 ± 3.8 vs 18.6 ± 4.2 vs 23.7 ± 6.2 (p = 0.015) I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 53.0 ± 7.8 vs 62.3 ± 13.7 vs 23.7 ± 6.2 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 6.5 ± 1.8 vs 6.0 ± 3.9 vs 10.2 ± 4.3 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 4.8 ± 3.5 vs 4.9 ± 5.8 vs 5.6 ± 4.7 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 2395 ± 1079 vs 2202 ± 874 vs 2251 ± 927 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 22.1 ± 14.0 vs 9.7 ± 7.1 vs 37.8 ± 70.8 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 11.1 ± 13.7 vs 12.3 ± 19.9 vs 20.3 ± 23.9 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 55.1 ± 43.7 vs 31.9 ± 29.0 vs 95.1 ± 159.3 I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 69.5 ± 69.8 vs 54.4 ± 60.8 vs 150.6 ± 140.1 | | 4 | Ho et al. [31] | Women with laparoscopically and histologically confirmed endometriosis (n = 17) r‐ASRM stages: n = 3 – I/II; n = 14 – III/IV. Menstrual phase: follicular | Women without endometriosis (n = 18) Menstrual phase: follicular | Concentration of IFN‐γ (T‐h1) in peritoneal fluid Concentration of TNF‐α (T‐h1) in peritoneal fluid Concentration of IL‐6 in peritoneal fluid Concentration of IL‐1β in peritoneal fluid | endometriosis group vs control group −0.30 ± 0.23 vs 0.46 ± 0.39 (p = 0.046) endometriosis group vs control group −8.71 ± 12.7 vs 3.66 ± 2.51 (p = 0.015) endometriosis group vs control group −103 ± 92 vs 33.0 ± 18.4 (p = 0.0007) endometriosis group vs control group −6.27 ± 21.21 vs 0.33 ± 0.66 (p = 0.037) | | 5 | Gogacz et al. [28] | Women with laparoscopically and histologically confirmed endometriosis (n = 26) r‐ASRM stages: n = 11 – I; n = 10 – II; n = 5 – III/IV. Menstrual phase: follicular | Women without endometriosis (n = 18) Menstrual phase: follicular | Concentration of Th17 in peritoneal fluid | endometriosis group vs control group −3.69 (p = 0.02) vs 11.54 (p = 0.01) | | 6 | Galandrini et al. [42] | Women with laparoscopically and histologically confirmed endometriosis (n = 20) r‐ASRM stages: n = 11 – III; n = 9 – IV. Menstrual phase: n = 13 ‐ follicular; n = 7 ‐ luteal | Women without endometriosis (n = 13) Menstrual phase: n = 7 ‐ follicular; n = 6 ‐ luteal | Concentration of NK in peritoneal fluid | endometriosis group vs control group −75.9 ± 8.2 vs 52.1 ± 16.3 (p < 0.0001) | | 7 | Antsiferova et al. [29] | Women with laparoscopically and histologically confirmed endometriosis (n = 15) r‐ASRM stages: not reported Menstrual phase: follicular | Women without endometriosis (n = 20) Menstrual phase: follicular | Concentration of CD4+ cells IL‐2 (Th) in peripheral blood Concentration of IL‐4 in peripheral blood Concentration of IL‐10 in peripheral blood | endometriosis group vs control group −2.16 ± 0.48 vs 1.52 ± 0.31 (p < 0.01) endometriosis group vs control group −11.47 ± 1.33 vs 6.08 ± 0.55 (p < 0.01) endometriosis group vs control group – 1.81 ± 1.98 vs 5.25 ± 0.5 (p < 0.01) | | 8 | Zhang et al. [34] | Women with laparoscopically and histologically confirmed endometriosis (n = 22) r‐ASRM stages: n = 4 – I; n = 4 – II; n = 9 – III; n = 5 – IV. Menstrual phase: n = 12 ‐ follicular; n = 10 ‐ luteal | Women without endometriosis (n = 22) Menstrual phase: n = 13 ‐ follicular; n = 9 ‐ luteal | Concentration of IL‐16 in peritoneal fluid Concentration of IL‐16 in peripheral blood | endometriosis group vs control group −290.5 (89.4–2181.2) vs 296.8 (88.3–1513.6) endometriosis group vs control group −539.4 (120.5–1775.1) vs 778.1 (147.9–2044.8) | | 9 | Yamamoto et al. [32] | Women with different stages of laparoscopically confirmed endometriosis (n = 64) r‐ASRM stages: n = 10 – I; n = 8 – II; n = 23 – III; n = 23 – IV. Menstrual phase: n = 31 ‐ follicular; n = 33 ‐ luteal | Women without endometriosis (n = 64) Menstrual phase: n = 26 ‐ follicular; n = 39 ‐ luteal | Concentration of IFN‐γ in peritoneal fluid Concentration of HLA‐ABC macrophages in peritoneal fluid Concentration of HLA‐DR macrophages in peritoneal fluid | endometriosis group vs control group −5.7 ± 3.4 vs 9.8 ± 4.6 (p < 0.005) endometriosis group vs control group – 70.7 ± 37.3 vs 88.2 ± 51.1 (p < 0.05) endometriosis group vs control group −18.0 ± 9.2 vs 24.6 ± 18.7 (p < 0.05) | | 10 | Xu et al. [35] | Women with laparoscopically and histologically confirmed endometriosis (n = 32) r‐ASRM stages: n = 9 – I; n = 10 – II; n = 9 – III; n = 4 – IV. Menstrual phase: not reported | Women without endometriosis (n = 28) Menstrual phase: not reported | The levels of RANTES in follicular fluid Concentration of MCP‐1 in follicular fluid | endometriosis group vs control group −460.4 ± 90.3 vs 243.8 ± 70.9 (p < 0.05) endometriosis group vs control group −330.0 ± 29.2 vs 420.5 ± 46.6 (p < 0.05) | | 11 | Witz et al. [36] | Women with laparoscopically and histologically confirmed endometriosis (n = 12) r‐ASRM stages: not reported Menstrual phase: follicular | Women without endometriosis (n = 23) Menstrual phase: n = 11 ‐ follicular; n = 12 ‐ luteal | Concentration of CD4+ (Th) cells in ectopic and eutopic endometrium Concentration of CD8+ (Tk) cells in ectopic and eutopic endometrium Concentration of VLA‐1 (T‐lymphocytes) cells in ectopic and eutopic endometrium Concentration of CD56+ cells (NK) in ectopic and eutopic endometrium | endometriosis group vs proliferative phase control group vs secretory phase control group −6.2 ± 1.0 vs 2.6 ± 0.7 vs 2.5 ± 0.5 (p < 0.01) endometriosis group vs proliferative phase control group vs secretory phase control group −6.4 ± 0.8 vs 3.1 ± 0.5 vs 2.6 ± 0.4 (p < 0.01) endometriosis group vs proliferative phase control group vs secretory phase control group −4.7 ± 0.7 vs 3.0 ± 0.5 vs 1.6 ± 0.2 (p < 0.01) endometriosis group vs proliferative phase control group vs secretory phase control group −1.8 ± 0.6 vs 3.4 ± 0.5 3.5 ± 0.8 (p < 0.05) | | 12 | Tanaka et al. [24] | Women with laparoscopically confirmed endometriosis (n = 27) r‐ASRM stages: not reported Menstrual phase: n = 13 ‐ follicular; n = 11 – luteal; n = 3 ‐ ovulation | Women without endometriosis (n = 28) Menstrual phase: n = 11 ‐ follicular; n = 13 ‐ luteal; n = 4 ‐ ovulation | Proportion of total Treg‐cells in ectopic and eutopic endometrium Proportion of activated Treg‐cells in ectopic and eutopic endometrium | endometriosis group vs control group −8.7 vs 11.2 (p < 0.01) endometriosis group vs control group −1.9 vs 5.0 (p < 0.01) | | 13 | Oosterlynck et al. [44] | Women with laparoscopically and histologically confirmed endometriosis (n = 24) r‐ASRM stages: n = 9 – I; n = 9 – II; n = 6 – III/IV. Menstrual phase: Luteal | Women without endometriosis (n = 10) Menstrual phase: luteal | Concentration of NK in ectopic and eutopic endometrium | I stage of endometriosis group vs II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 52.4 ± 11.7 vs 44.9 ± 10.6 vs 39.8 ± 11.2 vs 62.2 ± 8.5 (p < 0.002) | | 14 | Olkowska‐Truchanowicz et al. [26] | Women with laparoscopically and histologically confirmed endometriosis (n = 17) r‐ASRM stages: III/IV. Menstrual phase: follicular | Women without endometriosis (n = 15) Menstrual phase: follicular | Total concentration of CD4+ cells (T‐helpers) in peritoneal fluid Proportion of CD25+ FOXP3+ cells in peripheral blood Proportion of CD25+ FOXP3+ cells in peritoneal fluid Proportion of CD25low FOXP3+ cells in peripheral blood Proportion of CD25low FOXP3+ cells in peritoneal fluid Proportion of CD25high FOXP3+ cells in peripheral blood Proportion of CD25high FOXP3+ cells in peritoneal fluid | endometriosis group vs control group −4.1 vs 6.0 (p = 0.07) endometriosis group vs control group −4.4 ± 2.39 vs 5.2 ± 1.61 (p = 0.4) endometriosis group vs control group −6.1 ± 3.5 vs 3.4 ± 1.1 (p = 0.003) endometriosis group vs control group −3.3 ± 2.8 vs 3.7 ± 2.1 (p = 0.95) endometriosis group vs control group −2.7 ± 1.5 vs 1.2 ± 1.7 (p = 0.015) endometriosis group vs control group −0.8 ± 0.7 vs 1.6 ± 1.5 (p = 0.021) endometriosis group vs control group −3.1 ± 2.2 vs 2.0 ± 1.2 (p = 0.014) | | 15 | Mier‐Cabrera et al. [33] | Women with laparoscopically confirmed endometriosis (n = 32) r‐ASRM stages: I/ II. Menstrual phase: follicular | Women without endometriosis (n = 30) Menstrual phase: follicular | Concentration of CD4+ cells IFN‐γ (Th) in peripheral blood Concentration of CD4+ cells IFN‐γ (Th) in peritoneal fluid Concentration of CD4+ cells IL‐2 (Th) in peripheral blood Concentration of CD4+ cells IL‐2 (Th) in peritoneal fluid Concentration of CD8+ cells IFN‐γ (Tk) in peripheral blood Concentration of CD8+ cells IFN‐γ (Tk) in peritoneal fluid Concentration of CD8+ cells IL‐2 (Tk) in peripheral blood Concentration of CD8+ cells IL‐2 (Tk) in peritoneal fluid | endometriosis group vs control group −5.34 ± 1.94 vs 9.01 ± 4.02 (p < 0.001) endometriosis group vs control group −8.26 ± 3.25 vs 14.67 ± 3.03 (p < 0.001) endometriosis group vs control group −4.74 ± 2.51 vs 5.28 ± 2.24 (p < 0.001) endometriosis group vs control group −13.28 ± 3.59 vs 18.06 ± 3.72 (p < 0.001) endometriosis group vs control group −6.17 ± 1.85 vs 6.59 ± 1.69 (p < 0.001) endometriosis group vs control group −6.17 ± 1.85 vs 21.49 ± 5.75 (p < 0.001) endometriosis group vs control group −4.03 ± 2.24 vs 4.68 ± 2.1 (p < 0.001) endometriosis group vs control group −8.43 ± 2.77 vs 13.59 ± 3.52 (p < 0.001) | | 16 | Lukács et al. [21] | Women with laparoscopically and histologically confirmed endometriosis (n = 26) r‐ASRM stages: I/ II. Menstrual phase: follicular | Women without endometriosis (n = 23) Menstrual phase: follicular | Phagocytosis index of neutrophil granulocytes in peripheral blood Phagocytosis index of monocytes in peripheral blood | endometriosis group vs control group −1.80 ± 0.36 vs 3.77 ± 0.38 (p < 0.0001) endometriosis group vs control group −1.73 ± 0.72 vs 3.68 ± 0.37 (p < 0.0001) | | 17 | Malutan et al. [37] | Women with laparoscopically and histologically confirmed endometriosis (n = 80) r‐ASRM stages: n = 3 – II; n = 30 – III; n = 47 – IV. Menstrual phase: not reported | Women without endometriosis (n = 80) Menstrual phase: not reported | Concentration of IL‐1β in peripheral blood Concentration of IL‐6 in peripheral blood Concentration of TNF‐α in peripheral blood | endometriosis group vs control group −10.777 vs 3.039 (p = 0.002) endometriosis group vs control group −183.027 vs 70.043 (p < 0.001) endometriosis group vs control group −131.326 vs 75.285 (p = 0.015) | | 18 | Oosterlynck et al. [43] | Women with laparoscopically and histologically confirmed endometriosis (n = 23) AFS stages: n = 18 – I; n = 9 – II; n = 5 – III; n = 3 – IV. Menstrual phase: luteal | Women without endometriosis (n = 21) Menstrual phase: luteal | Concentration of NK in peritoneal fluid | I stage of endometriosis group vs II stage of endometriosis group vs III/IV stages of endometriosis group vs control group 7.5 ± 5.3 vs 5.1 ± 4.6 vs 4.3 ± 4.7 vs 15.5 ± 8.1 ( p < 0.0002) | | 19 | Podgaec et al. [30] | Women with laparoscopically and histologically confirmed endometriosis (n = 65) r‐ASRM stages: n = 28 – I/II; n = 37 – III/IV. Menstrual phase: not reported | Women without endometriosis (n = 33) Menstrual phase: not reported | Concentration of IFN‐γ (T‐h1) in peritoneal fluid Concentration of TNF‐α (T‐h1) in peritoneal fluid Concentration of IL‐4 (T‐h2) in peritoneal fluid Concentration of IL‐10 (T‐h2) in peritoneal fluid | endometriosis group vs control group −3.1 vs 1.4 (p = 0.036) endometriosis group vs control group −1.7 vs 0 (p = 0.557) endometriosis group vs control group −1.7 vs 0 (p = 0.557) endometriosis group vs control group −28.6 vs 25.7 (p < 0.005) | | 20 | Punnonen et al. [40] | Women with laparoscopically and histologically confirmed endometriosis (n = 15) r‐ASRM stages: n = 6 – I; n = 4 – II; n = 1 – III; n = 4 – IV. Menstrual phase: follicular | Women without endometriosis (n = 12) Menstrual phase: follicular | Concentration of IL‐6 in peritoneal fluid Concentration of IL‐10 in peritoneal fluid | endometriosis group vs control group −797 ± 407 vs 133 ± 38 (p < 0.02) endometriosis group vs control group −241 ± 38 vs 128 ± 21 (p < 0.05) | | 21 | Hanada et al. [25] | Women with laparoscopically and histologically confirmed endometriosis (n = 28) r‐ASRM stages: n = 7 – I; n = 6 – II; n = 11 – III; n = 4 – IV. Menstrual phase: n = 12 ‐ follicular; n = 16 ‐ luteal. | Women without endometriosis (n = 20) Menstrual phase: n = 10 ‐ follicular; n = 10 ‐ luteal. | Concentration of CD45RA+ FoxP3low resting Tregs in peritoneal fluid Concentration of CD45RA− FoxP3high effector Tregs in peritoneal fluid Proportion of LAP+ macrophages in peritoneal fluid Concentration of TGF‐β in peritoneal fluid | endometriosis group vs control group −0.60 vs 0.25 (p = 0.02) endometriosis group vs control group −3.4 vs 1.7 (p < 0.01) endometriosis group vs control group −6.2 vs 21.2 (p < 0.01) endometriosis group vs control group −1.08 vs 0.75 (p < 0.01) | | 22 | Gogacz et al. [39] | Women with laparoscopically and histologically confirmed endometriosis (n = 26) r‐ASRM stages: n = 11 – I; n = 10 – II; n = 5 – III/IV. Menstrual phase: follicular. | Women without endometriosis (n = 16) Menstrual phase: follicular. | Concentration of CD95+ in peritoneal fluid Concentration of HLA‐DR+ in peritoneal fluid | endometriosis group vs control group −20.1 ± 15.7 vs 6.6 ± 10.1 (p < 0.05) endometriosis group vs control group −85.4 ± 7.3 vs 62.2 ± 31.1 (p <0.05) | | 23 | Keenan et al. [41] | Women with laparoscopically and histologically confirmed endometriosis (n = 37) r‐ASRM stages: n = 25 – I/II; n = 12 – III/IV. Menstrual phase: follicular. | Women without endometriosis (n = 25) Menstrual phase: follicular. | Concentration of IL‐6 in peritoneal fluid | I/II stage of endometriosis group vs III/IV stages of endometriosis group vs control group −443.4 ± 147.5 vs 809.26 ± 282.0 vs 102.9 ± 38.7 (p < 0.015) | | 24 | Zheng et al. [23] | Tissue samples from women undergoing laparoscopic surgery for III‐IV stage endometriosis (n = 25) r‐ASRM stages: III/IV. Menstrual phase: follicular. | Women without endometriosis (n = 15) Menstrual phase: follicular. | Total concentration of CD4+ cells (T‐helpers), gamma delta T‐cells, monocytes, M2‐ macrophages, mast cells in ectopic and eutopic endometrium Total concentration of CD8+ (T‐killers), NK cells, Tregs in ectopic and eutopic endometrium | A statistically significant increase of Th17 concentration in endometriosis group (p < 0.05). A statistically significant reduction in endometriosis group (p < 0.05) | According to the Cochrane Handbook for Systematic Reviews of Interventions, three reviewers (S.B., K.K. and K.M.) independently assessed the risk of bias in each of the included studies using ROBINS‐I for non‐randomized studies [19]. Any disagreements were resolved by discussion with the fourth author (L.P.). Visualization tools were created by the ROBVIS app [20]. This application created “traffic light” graphs of domain‐level judgments for each result and weighted bar graphs of the distribution of risk‐of‐bias judgments within each bias domain. Based on these tools, 50% of trials had low, 46%—moderate, and 4 %—serious risks of bias (Figure 2). Although Lukács et al., was assessed as having a high risk of bias in Domain 5 (missing data), the study was included in the review because it had a low risk of bias across all remaining domains and made a unique contribution to the assessment of monocyte phagocytic activity in endometriosis [21]. 3.1. T‐Regulatory Lymphocytes T‐regulatory lymphocyte alterations in endometriosis show a compartment‐specific pattern across systemic, peritoneal, and endometrial compartments [22, 23, 24, 25, 26]. In peripheral blood, Le et al., reported a significant reduction in inducible Tregs (p < 0.05) [22] Zheng et al. found that regulatory T cells were downregulated in ectopic lesions of patients with endometriosis (p < 0.05) [23]. Similarly, Tanaka et al. demonstrated significantly lower proportions of both total and activated Tregs in ectopic and eutopic endometrium [24]. In peritoneal fluid, findings were also inconsistent across subpopulations. Ho et al. reported reduced CD25+CD4+CD3+ concentrations, with relatively higher counts in stages I–II [27]. Hanada et al. found significantly elevated CD45RA+FoxP3low resting Tregs and CD45RA−FoxP3high effector Tregs in peritoneal fluid [25]. Olkowska‐Truchanowicz et al. observed a compartment‐dependent pattern: CD25low and CD25high FOXP3+ cell proportions were increased in peritoneal fluid but decreased in peripheral blood of endometriosis patients [26]. Collectively, these findings indicate that Treg dysregulation in endometriosis is compartment dependent and involves distinct subpopulations, making a single unified interpretation difficult. 3.2. T‐Helper Lymphocytes T‐helper lymphocyte alterations in endometriosis are compartment dependent and involve both changes in CD4+ cell distribution and helper T‐cell cytokine profiles. Olkowska‐Truchanowicz et al. reported reduced CD4+ T‐helper cell concentrations in peritoneal fluid [26], whereas Zheng et al. found increased CD4+ T‐cell proportions in ectopic lesions, suggesting local redistribution rather than a uniform systemic shift [23]. Th17/Treg balance was also disrupted: Le et al. demonstrated increased Th17‐cell concentrations in peripheral blood with a consequently reduced Treg/Th17 ratio (p < 0.05) [22], whereas Gogacz et al. reported lower Th17 levels in peripheral blood, highlighting the inconsistency of the available data [28]. Cytokine data related to T‐helper cells were similarly conflicting across biological compartments. Ho et al. reported reduced IL‐4 in peripheral blood and peritoneal fluid [27], whereas Antsiferova et al. found the opposite [29]. Podgaec et al. further demonstrated a distinct Th‐cytokine pattern in peritoneal fluid, with significantly increased IFN‐γ and IL‐10 concentrations, whereas IL‐4 and TNF‐α did not differ significantly between groups, underscoring the heterogeneity of helper T‐cell‐associated cytokine findings in endometriosis [30]. IFN‐ was more consistently decreased: Ho et al. [31], Yamamoto et al. [32], and Mier‐Cabrera et al. reported lower levels in peritoneal fluid, and Mier‐Cabrera et al. also found reduced peripheral blood levels [33]. Ho et al. also showed decreased IL‐5 in both compartments [27], Zhang et al. reported IL‐16 measurements in both peritoneal fluid and peripheral blood [34], Xu et al. found elevated RANTES in follicular fluid [35], and Witz et al. observed increased VLA‐1 expression in ectopic endometrium [36]. In our systematic review and meta‐analysis, based on quantitative synthesis, IL‐4 concentration was equal in study groups (MD = 1.32, 95% CI: −15.00 to 17.63, p = 0.87). The heterogeneity for this comparison was 39%. However, this meta‐analysis included 2 studies evaluating 75 patients in 1997 and 2005. (Figure 3A.) 3.3. T‐Killer Lymphocytes CD8+ cytotoxic T‐lymphocytes in endometriosis appear to exhibit functional suppression across multiple biological compartments. Mier‐Cabrera et al. reported significantly reduced IL‐2 concentrations, a marker of cytotoxic T‐cell activity, in both peritoneal fluid and peripheral blood of patients with endometriosis [33]. The same study also showed decreased IFN‐γ levels in both compartments, while Yamamoto et al. independently confirmed. IFN‐γ concentration in peritoneal fluid [32]. Additional findings suggest that T‐killer‐cell‐related pathways may also be altered at the tissue level. Witz et al. demonstrated increased VLA‐1 expression in ectopic endometrium compared with eutopic endometrium during the proliferative and secretory phases [36], and Xu et al. reported elevated RANTES concentrations in follicular fluid of patients with endometriosis [35]. Although these markers are not limited exclusively to CD8+ cells, together they support the involvement of cytotoxic T‐lymphocyte‐associated immune mechanisms in the pathogenesis of endometriosis. Overall, the available evidence points to a suppressed CD8+T‐cell response in endometriosis, which may contribute to impaired immune surveillance and facilitate the persistence of ectopic endometrial cells. 3.4. Monocytes Monocyte dysfunction in endometriosis is evidenced by both altered cell counts and impaired functional activity. Lukács et al. demonstrated a significantly reduced phagocytic index of monocytes in peripheral blood of patients with endometriosis, while Xu et al. reported decreased MCP‐1 concentrations in follicular fluid, suggesting disrupted monocyte recruitment. Zheng et al. additionally identified elevated monocyte levels in the endometriosis group compared with healthy controls, which, together with the reduced phagocytic capacity, may reflect dysfunctional monocyte accumulation rather than effective immune activation. Monocyte‐derived cytokines were also consistently elevated in endometriosis. Ho et al. and Ho et al. reported significantly increased IL‐1β concentrations in both peritoneal fluid and peripheral blood, alongside elevated TNF‐α levels in peripheral blood. These pro‐inflammatory mediators may promote the survival and progression of ectopic endometrial lesions. Monocyte alterations in endometriosis involve both impaired functional activity and changes in cell abundance, indicating that these cells may contribute to disease persistence through ineffective immune surveillance rather than adequate clearance of ectopic tissue. Lukács et al. demonstrated a significantly reduced phagocytic index of peripheral blood monocytes in patients with endometriosis, suggesting compromised monocyte effector function [21], while Zheng et al. identified elevated monocyte levels in the endometriosis group compared with healthy controls, consistent with abnormal accumulation of these cells despite impaired activity [23]. Evidence of altered monocyte recruitment was also reported by Xu et al., who found decreased MCP‐1 concentrations in follicular fluid of patients with endometriosis [35]. Although lower MCP‐1 might appear inconsistent with monocyte accumulation, these findings may reflect compartment‐specific dysregulation of chemotactic signaling rather than a uniform change across all biological fluids. Monocyte‐associated inflammatory signaling was further supported by cytokine data. Ho et al. and Ho et al. reported significantly increased IL‐1β concentrations in both peritoneal fluid and peripheral blood in women with endometriosis, while TNF‐α levels were also elevated in peripheral blood [27, 31]. These findings are further supported by Malutan et al., who demonstrated significantly elevated peripheral blood concentrations of IL‐1β, IL‐6, and TNF‐α in women with endometriosis, reinforcing the presence of a systemic pro‐inflammatory monocyte/macrophage‐associated cytokine profile [37]. Together, these findings suggest that monocytes in endometriosis are characterized not by effective protective immune function, but by dysfunctional activation accompanied by a persistent pro‐inflammatory profile that may support lesion survival and progression. 3.5. Macrophages Macrophage dysregulation in endometriosis is characterized by both phenotypic polarization and altered immune activity across local inflammatory compartments. Zheng et al. identified an increased proportion of M2‐like macrophages in ectopic endometrial lesions, suggesting a shift toward an anti‐inflammatory, pro‐fibrotic phenotype that may favor lesion persistence rather than effective immune clearance [23]. In peritoneal fluid, additional phenotypic abnormalities were reported by Kusume et al., who demonstrated divergent HLA‐subpopulation patterns, with HLA‐ABC macrophages increased and HLA‐DR macrophages decreased in patients with endometriosis [38], while Hanada et al. found a significantly reduced proportion of LAP+ macrophages, further supporting impaired immunoregulatory function within the peritoneal microenvironment [25]. Gogacz et al. additionally demonstrated increased Fas‐mediated apoptosis of peritoneal fluid macrophages in patients with endometriosis, suggesting that macrophage dysregulation in this disease may involve not only altered phenotype but also impaired survival and turnover of these cells [39]. Cytokine findings also indicate functionally altered macrophage responses. Yamamoto et al. reported reduced IFN‐ concentrations in peritoneal fluid [32], whereas Ho et al., Punnonen et al., and Keenan et al. consistently demonstrated elevated IL‐6 levels in peritoneal fluid of women with endometriosis [31, 40, 41]. Keenan et al. additionally showed that IL‐6 concentrations were higher in stage III/IV disease than in stage I/II disease, suggesting that macrophage‐associated inflammatory activation may become more pronounced with advancing disease severity [41]. Punnonen et al. also reported elevated IL‐10 concentrations in peritoneal fluid, suggesting that macrophage‐associated cytokine activation in endometriosis may extend beyond pro‐inflammatory mediators to include compensatory anti‐inflammatory signaling [40]. Our secondary analysis aimed to compare the concentration of HLA‐macrophages in peritoneal fluid between the endometriosis and control groups. This comparison consisted of 2 subgroup analyses: assessing the concentration of HLA‐DR and HLA‐ABC macrophages. Totally this comparison included 5 studies involving 492 patients (MD = 2.62, 95% CI: −8.98 to 3.73, p = 0.42). Overall heterogeneity was 86%. Thus, macrophages concentration in endometriosis group were less than in controls, but not statistically significant (p = 0.42). Meta‐analysis of HLA‐ABC macrophages included 2 studies involving 225 patients. In the result, they were less in endometriosis group, but not statistically significant (MD = −6.84, 95% CI: −23.94 to 10.26, p = 0.43). Heterogeneity for this comparison was 80%. (Figure 3B.) The IL‐6 concentration in peritoneal fluid between endometriosis and control groups was assessed in third meta‐analysis, that included 3 studies evaluating 112 patients. IL‐6 was higher in endometriosis group compared to controls (MD = 338.00, 95% CI: 85.02 to 590.98, p = 0.009). The heterogeneity for this comparison was 97%. (Figure 3C.) 3.6. Natural Killers Natural killer cell dysregulation in endometriosis demonstrates a pronounced compartment‐dependent pattern, with discrepant findings in peritoneal fluid but more consistent abnormalities within endometrial tissue. In peritoneal fluid, Galandrini et al. reported a significantly increased NK‐cell concentration in patients with endometriosis [42], whereas Oosterlynck et al. observed reduced NK‐cell levels and further showed that this reduction became more pronounced with disease progression, indicating that NK‐cell alterations in the peritoneal cavity may vary according to disease stage and study population [43]. In contrast, findings in endometrial tissue more consistently support reduced NK‐cell representation at ectopic lesions. Witz et al. demonstrated a significantly lower concentration of CD56+ cells in ectopic endometrium compared with normal eutopic endometrium in both the proliferative and secretory phases [36], and similar results were reported by Oosterlynck et al. who found reduced NK‐cell levels in ectopic endometrium across stage I, stage II, and stage III/IV disease compared with controls [44]. Zheng et al. further supported this pattern by showing that resting NK cells were significantly reduced in ectopic endometrial samples from patients with endometriosis [23]. Functional impairment of NK‐cell activity is also suggested by cytokine data. As described above, several studies reported decreased IFN‐ concentrations in peritoneal fluid, a finding that may reflect diminished NK‐cell cytotoxic function within the peritoneal microenvironment rather than merely quantitative changes in cell number [31, 32, 33]. Taken together, these observations suggest that the role of NK cells in endometriosis is defined not only by altered abundance, but also by impaired immune surveillance at sites where ectopic lesions develop and persist. Our fourth analysis aimed to compare the NK‐cells level in peritoneal fluid between endometriosis and control groups and included 3 studies evaluating 102 patients in 1992, 1997, 2008. NK‐cells were higher in endometriosis group, but not significantly (MD = 6.75, 95% CI: −12.42 to 25.91, p = 0.49). The heterogeneity for this comparison was 96%. (Figure 3D.) The level of NK‐cells in ectopic endometrium of patients with endometriosis and eutopic endometrium of controls was evaluated in fifth analysis, that consisted of 2 studies including 58 patients. Thus, NK‐cells in ectopic endometrium of patients with endometriosis were less than in eutopic endometrium of controls (MD = −9.12, 95% CI: −24.39 to 6.15, p = 0.24). The heterogeneity for this comparison was 95%. (Figure 3E.) 4. Discussion Hypotheses proposing immune dysfunction as a potential etiological factor in endometriosis have become increasingly prominent in the recent literature. Components of both innate and adaptive immunity, as well as cellular and humoral immune responses, have been extensively investigated for their role in the pathogenesis of this disease [44]. It is assumed that mediators secreted by immune cells contribute to the progression of endometriosis by promoting neoangiogenesis and disrupting immunoregulatory mechanisms [45, 46]. However, the clinical heterogeneity of endometriosis complicates the standardization of diagnostic criteria and treatment protocols, both of which are essential for clinical research and the development of evidence‐based medical approaches [47]. The diverse manifestations of the disease hinder the design and implementation of large‐scale randomized controlled trials (RCTs) capable of generating high‐quality, generalizable evidence for the broader patient population. Progress in this field requires the development of more accurate animal models, the application of integrative and multidisciplinary research strategies, and the implementation of standardized surgical techniques and publication guidelines. In addition, long‐term clinical studies are needed to improve understanding of both the fundamental and clinical aspects of endometriosis while minimizing methodological limitations [48, 49, 50, 51, 52, 53, 54]. Several previously published systematic reviews have also examined the role of the immune system in the pathogenesis of endometriosis. For example, the Kisovar et al. study evaluated the role of CD8+ immune cells in patients with endometriosis and showed an increased concentration of CD8+ T cells in endometriotic lesions, which corresponds to our results. Also, increased cytotoxicity of these cells was obtained in the menstrual blood of patients, as was the amount of CD8+ memory cells in the eutopic endometrium of patients with endometriosis [55]. The involvement of another key effector population, natural killer cells, was investigated by Reis et al. study. The authors reported overexpression of inhibitory NK‐cell receptors together with reduced expression of NK‐activating receptors and natural cytotoxicity receptors, changes that may impair the elimination of endometriotic cells from the peritoneal cavity and thereby facilitate their implantation and progression [56]. Similar conclusions were reported by Fukui et al., who showed that abnormal expression of NK‐cell receptors and cytokines is involved in the development of endometriosis [57]. Alterations in CD4+ T‐lymphocyte populations in patients with endometriosis were investigated by Yang and Zhuang in 2023 study, who identified significant changes exclusively in peritoneal fluid [58]. According to their findings, the concentration of CD4+ immune cells in the peritoneal fluid was significantly lower in the endometriosis group, which is consistent with the results of our review. However, the difference in peripheral blood CD4+ cell levels between the endometriosis and control groups was not statistically significant. It should be noted that our own findings in this area were not entirely consistent: Antsiferova et al.’s in 2005 demonstrated increased levels of CD4+ cells IL‐2 [29], but in 2010 Mier‐Cabrera et al.’s revealed that these cells were decreased, the same was the concentration of CD4+ cells IFN‐γ [33]. Interestingly, the concentration of CD4+ cells in the ectopic endometrium of patients was significantly higher than in the eutopic endometrium of healthy women, as proved by the Witz et al. in 1994 study [36]. Another component of cellular immunity, dendritic cells, and their role in the pathogenesis of endometriosis were evaluated by Laginha et al. in 2022 [59]. The data show that dendritic cells are able to secrete proangiogenic factors and thus enhance endothelial cell migration in endometriosis. Additionally, the pathological microenvironment may induce immature dendritic cells into a macrophage phenotype. In the Vallvé‐Juanico et al. study, the immune endometrial microenvironment of women with endometriosis was analyzed, and researchers have come to the conclusion that macrophages, immature dendritic cells, T‐regulatory lymphocytes as well as NK cells are dysregulated due to the disease [60]. These observations are in agreement with the findings of our systematic review. Elevated TGF‐β levels in peritoneal fluid have been linked to fibrogenesis in endometriosis, as shown by Viganò et al. [61]. Peritoneal macrophages secrete TGF‐β, activating the TGF‐β1/Smad3 pathway in endometriotic cells and promoting epithelial‐to‐mesenchymal transition (EMT), fibroblast‐to‐myofibroblast transdifferentiation, and smooth muscle metaplasia—processes that drive collagen deposition and fibrosis. Our review also identified increased IL‐1β and IL‐6 levels, which are associated with pelvic adhesions. The role of macrophages was further confirmed by Laganà et al., who reported a shift from pro‐inflammatory M1 to anti‐inflammatory M2 macrophages with advancing disease stages favoring fibrosis [62]. Similar findings were presented by Ramírez‐Pavez et al. [63]. An increased concentration of TNF‐α in the peritoneal fluid of patients with endometriosis was demonstrated in the study by Kolanska et al., which aligns with the findings of our systematic review. Furthermore, this study evaluated the involvement of mast cells, neutrophils, eosinophils, dendritic cells, and the complement system as key components in the pathogenesis of endometriosis [64]. Specifically, mast cells release pro‐inflammatory mediators, neutrophils secrete pro‐angiogenic cytokines, dendritic cells are believed to contribute to the expansion of endometrial lesions, and eosinophil concentrations as well as levels of various complement components are elevated in patients with endometriosis. The findings of the present systematic review and meta‐analysis carry important clinical implications for the management of endometriosis. A clearer understanding of the role of cellular immunity in ectopic lesion progression may support the development of noninvasive early biomarkers. Several diagnostic models have already been proposed, including the RANTES/IL‐6 ratio, assays measuring CCR1, MCP‐1, and CA‐125, and plasma‐based tests assessing cytotoxic T lymphocytes and natural killer cells [8, 16]. These immunocytes and cytokines are also promising therapeutic targets. Treg adoptive transfer may help correct local immune dysregulation by suppressing ectopic lesion growth and reducing helper T‐cell‐associated pro‐inflammatory cytokines [65]. Macrophage depletion or phenotypic reprogramming is another potential strategy, including CD47–SIRP‐α blockade or the use of agents such as celastrol, MS‐275, and dexverapamil [66, 67]. Because macrophages contribute to oxidative stress, antioxidants such as curcumin may reduce TNF‐α, IL‐1β, IL‐6, and IL‐8 overexpression [60]. In addition, M1 macrophage‐derived nanovesicles may repolarize pro‐fibrotic M2 macrophages toward an M1 phenotype, thereby inhibiting lesion migration, invasion, and neoangiogenesis [68]. NK cells may also be targeted to improve immune surveillance in the peritoneal cavity. Neutralizing soluble MICA can restore NK‐cell degranulation and IFN‐γ production by preventing NK‐cell suppression [69]. Other approaches include blocking inhibitory receptors such as KIR2DL1, LILRB1/2, and NKG2A, or suppressing NK‐cell‐derived TGF‐β [70]. In animal models, BCG vaccination increases NK‐cell recruitment and cytotoxicity, whereas intravenous intralipid may improve impaired NK‐cell function [11, 71, 72]. Targeting cytokine signaling offers another therapeutic avenue. Anti‐IL‐6 receptor monoclonal antibodies reduce chronic inflammation, decrease ectopic lesion volume, and induce atrophy of the ectopic endometrial epithelium [73]. These approaches may also complement hormonal therapy. Progestins, the basis of current hormonal treatment, have anti‐inflammatory and immunomodulatory effects. They suppress NF‐κB signaling and modulate inflammatory cascades through interactions with HSP90 and immunophilins such as FKBP51 and FKBP52, thereby reducing mitogenic signaling and promoting immune tolerance [74]. In summary, modulation of cellular immunity may help overcome treatment resistance, normalize the peritoneal microenvironment, and improve clinical outcomes. Although these strategies are not yet part of routine practice, further research may enable personalized therapy for patients with endometriosis. However, there are some limitations. First of all, many of the studies included in this review are outdated. Also, during the analysis, a high heterogeneity of the studied groups was obtained, which significantly complicated the meta‐analysis. Moreover, some studies did not specify which biomarkers they examined in relation to producing cells, and some publications did not provide numerical values of their results, which made it difficult to conduct a meta‐analysis. Some of the studies divided the participants according to the stage of endometriosis, while the other part did not provide such data, which made it difficult to compare the concentration of biomarkers in these papers. In the same way, part of the studies divided the control group of patients relative to the stage of their menstrual cycle, while the other part did not do this when assessing the concentrations of biomarkers in the eutopic endometrium. After all, many studies have assessed the concentrations of the studied biomarkers in only one biological sample, whereas a review of these indicators in both peritoneal fluid and peripheral blood, ectopic and eutopic endometrium, would contribute to a holistic view of immune dysregulation in endometriosis. The high heterogeneity of studies in endometriosis research plays a crucial role in the evidence‐based approach to its management. Clinical heterogeneity complicates the standardization of diagnostic criteria and treatment protocols, which are fundamental to evidence‐based medicine. The diverse manifestations of endometriosis and insufficient noninvasive diagnostics make it difficult to design and conduct large‐scale, RCTs that can provide high‐quality evidence applicable to all patients. Future research should focus on high‐quality studies with larger cohorts, evaluating specific cellular immunity biomarkers in peritoneal fluid, blood, and endometrial tissues—while accounting for disease form, stage, menstrual cycle phase, and treatment status. Comparative analysis with healthy reproductive‐age women is essential. Further investigation of these markers may improve early, noninvasive diagnosis and support the development of immunotherapies targeting immune dysregulation and the pathological peritoneal environment. Special attention should be given to their role in peritoneal adhesion formation, a major cause of pain, infertility, and reduced quality of life. All of the above proves the importance of evaluating alterations in cellular immunity in the pathogenesis of endometriosis. 5. Conclusion Our systematic review and meta‐analysis assessed the role of cellular immune dysregulation in the pathogenesis of endometriosis. Based on the findings from the included studies, signaling pathways involving T lymphocytes, monocytes, macrophages, and natural killer cells are altered in patients with endometriosis. However, due to the limited quality of available studies and the high heterogeneity among study populations, performing meta‐analyses and synthesizing these data into evidence‐based guidelines for early, noninvasive diagnosis remains challenging. Quantitative synthesis of the data confirmed that IL‐6 levels are significantly elevated in the peritoneal fluid of endometriosis patients. Additionally, the NK cell level in ectopic endometrial tissue was found to be lower compared to eutopic endometrium in control group. Despite these limitations, our findings contribute to the growing support for the immune dysregulation hypothesis in endometriosis pathogenesis and may provide a foundation for the future use of immune biomarkers in the early, noninvasive diagnosis and treatment of endometriosis. Ethics Statement The authors confirm that the ethical policies of the journal, as noted on the journal's author guidelines page, have been adhered to. No ethical approval was required as this is a review article with no original research data. Conflicts of Interest The authors declare no conflicts of interest. Supporting information

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