Endometriosis and autoimmunity

The endometrial immune system differs from that of other mucosal and epithelial surfaces leading to contributing to the unique immune characteristics associated with endometriosis. The normal endometrium functions both as a barrier to pathogens, but also as a site for embryonic implantation, which requires tolerance of the semi-allogeneic fetus [ 39 , 40 ]. Additionally, the uterine immune system must coordinate tissue repair and regeneration associated with hormonal cycling and menstruation [ 40 ]. The human endometrium harbors a substantial number of resident immune cells [ 41 ]. Innate immune cells populating the endometrium include uterine NK (uNK) cells, mast cells, macrophages, dendritic cells (DC) and neutrophils [ 39 ]. The endometrium also serves as an active site for adaptive immunity, evidenced by the presence of lymphoid aggregates within the endometrial tissue, consisting of CD19+ B cells located in the inner core, surrounded by CD8+ CD4− T cells, and encased by an outer layer of macrophages [ 39 ]. When compared to women without endometriosis, the immune microenvironment in the eutopic endometrium in women with endometriosis is a markedly pro-inflammatory. As shown in Figure 1 , in endometriosis a macrophage M1 phenotype, compared to an anti-inflammatory macrophage M2 phenotype, alongside abnormal activity of uterine natural killer (uNK) cells and regulatory T-cells (Tregs) predominates [ 42 ]. In women without endometriosis, the uterine immune microenvironment varies in response to physiologic hormonal fluctuations across the menstrual cycle. However, this cycle-dependent variation is blunted within the eutopic endometrium of women with endometriosis and may be an important factor contributing to lesion establishment and maintenance from shed endometrium [ 43 , 44 ]. Indeed, the immune changes associated with endometriosis may contribute to dysregulated aspects of reproductive tract and endometrial function, including oocyte quality, fertilization, embryo quality, endometrial receptivity, implantation, and placentation, in affected people [ 4 , 11 – 13 , 45 , 46 ]. The resultant pro-inflammatory environment in the eutopic endometrium of individuals with endometriosis may interact with other gynecologic disorders to adversely influence reproductive outcomes. Intraovarian oxidative stress in an endometrioma may contribute to altered oocyte quality and embryonic incompetence, while diffuse adenomyosis in the myometrium may impair endometrial receptivity at the implantation interface [ 13 , 47 ]. Although the precise role of the adaptive immune system (T-cell and B-cell responses) in endometriosis is poorly understood, a marked, chronic inflammatory response within the peritoneal cavity is a requirement for the development of endometriosis. Notably, allotransplanted NOD/SCID mice that lack a functional immune system do not develop endometriotic lesions [ 48 ]. Higher concentrations of Type 17 helper (Th17) T-cells have been observed in the peritoneal fluid associated with endometriosis, and epidemiologic studies show an association between endometriosis and circulating autoantibodies [ 49 , 50 ]. T-regulatory lymphocytes (Tregs) are important in downregulating immune responses, and may play a role in endometriosis [ 51 ]. Disturbed Treg homeostasis, leading to increased systemic and local inflammation within ectopic and eutopic endometrium, is present in women with endometriosis. However, the specific contribution of different subsets of human Treg cells in suppressing the immune response in endometriosis as well as the specific characterization of the non-Treg (FOXP3lowCD45RA−) fraction have not yet been fully elucidated. Additionally, compared to eutopic endometrium, a lower ratio of Treg to Th17 T lymphocytes has been reported supporting the hypothesis that the endometriosis microenvironment results in a proinflammatory phenotype [ 52 ]. The microenvironment of endometriosis lesions is marked by a hyper-estrogenic state and elevated levels of reactive oxygen species (ROS), which promote lesion establishment and growth. This setting triggers immune and inflammatory responses, leading to the release of cytokines and chemokines as well as cellular adhesion and proliferation, promoted by release of NGF and VEGF, as shown in Figure 2 . Enrichment of active neutrophils, inflammasome activation, and enhanced complement C3 production stimulating mast cells have all been proposed as potential drivers of the proinflammatory peritoneal milieu that favor endometriosis lesion attachment, proliferation, and pain symptomatology [ 53 – 56 ]. Likely contributors to the dysregulated host immune surveillance in endometriosis include macrophages with low phagocytosis activity and diminished natural killer (NK) cells cytotoxicity in peripheral blood, peritoneal fluid, and endometrial tissue [ 57 , 58 ]. Various cytokines have been shown to be important in endometriosis pathogenesis and differentially expressed in patients with endometriosis compared to controls [ 21 , 59 ]. Vascularization plays a critical role in implantation and propagation of endometriosis lesions. Vascular endothelial growth factor (VEGF), a primary angiogenic factor, is expressed by the epithelial and stromal cells within the endometrium and endometriosis implants as well as by associated immune cells, especially neutrophils [ 60 ]. In animal models, angiogenesis inhibitors have been shown to blunt endometriosis lesion development [ 61 ]. Inflammasome activation is a common feature of autoimmune conditions and is responsible for tissue damage [ 62 ]. In endometriosis, persistent proinflammatory stimuli accompanied by high levels of estradiol likely fuel activation of the inflammasome and may contribute to pelvic pain via IL-1β and other inflammasome derived proinflammatory cytokines [ 55 , 63 ]. Elevated levels of interleukin-6 (IL-6) play a critical role in immune dysregulation contributing to impaired NK cell activity and reduced macrophage phagocytic capacity within the peritoneal cavity [ 64 , 65 ]. Increased proinflammatory cytokines and proangiogenic factors have been identified within peritoneal fluid of individuals with endometriosis and it is likely that these molecules amplify this immune dysfunction [ 66 , 67 ]. Surgical excision of lesions is associated with a temporary reduction in the systemic cytokine levels, including granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-8, and IL-10 adding to evidence of the critical role of immune signaling pathways in regulating this condition [ 68 ]. During the menstrual cycle, hemorrhage, and breakdown of ectopic endometrium from endometriosis lesions expels erythrocytes into the microenvironment of the peritoneum which, unlike the eutopic endometrium, is poorly equipped to manage the released heme and iron. As a result, ROS trigger oxidative stress, perpetuating immune dysregulation through activation of the NF-kB pathway [ 69 , 70 ]. The release of heme by ectopic endometrial tissue also suppresses macrophage phagocytic activity [ 71 ]. Dysregulation of macrophage phagocytosis through reduced expression of pattern recognition receptors in macrophages, has been shown to correlate with endometriosis disease activity and prognosis, supporting the important role for macrophage-mediated phagocytosis in endometriosis [ 65 , 72 – 74 ]. Dysregulated iron homeostasis leads to resistance to ferroptosis (a type of iron-dependent, non-apoptotic cell death), and prompts a localized immune and inflammatory reaction, resulting in the release of cytokines, chemokines, and prostaglandins [ 75 ]. Mitochondrial dysfunction has been documented in endometriosis tissues [ 78 , 79 ], and the heme rich environment in ectopic lesions. Mitochondrial dysfunction and ROS may arise or be perpetuated, in part, by the generation of mitochondrial oxidative stress [ 80 ] and metabolic dysfunction [ 80 ], including mTOR activation [ 81 ], loss of glutathione [ 82 ] and cysteine [ 83 ], all of which occur in endometriosis [ 84 , 85 ]. Similar mitochondrial dysfunction is seen in response to enhanced mitochondrial ROS and oxidized mitochondrial DNA in autoimmune diseases [ 86 , 87 ] lending further weight to the hypothesis that there may be common pathways of tissue injury in endometriosis and autoimmune diseases. Heightened ferroptosis, and enhanced levels of succinate resulting from hypoxia could partially explain mitochondrial alterations and propagation of endometriotic lesions [ 88 – 91 ], and certain mitochondrial DNA polymorphisms (mtDNA 16189 and the combination of mtDNA 16189 and 10398 variants) have been associated with increased likelihood of developing of endometriosis [ 92 ]. In animal models of endometriosis, treatment with antioxidants such as vanillin attenuates the size of endometriotic lesions [ 76 ], and thus supports a role for ROS and mitochondrial dysfunction in endometriosis. Hypoxic microenvironments also contribute to neoantigen generation, and this can further trigger autoimmune responses and propagate inflammation and neovascularization. In hypoxic conditions, oxidized mitochondrial DNA has potent type I interferon (IFN) and proinflammatory properties, and this hypoxia may well contribute to the known correlation seen between endometriosis and other autoimmune conditions such as systemic lupus erythematosus (SLE) [ 93 , 94 ], and rheumatoid arthritis. In addition to being a chronic inflammatory condition, endometriosis is a hormonally mediated estrogen-dependent, progesterone-resistant condition. Thus, hormonal modulation, with oral contraceptives, GnRH agonists, or androgens, are first line therapies for endometriosis and provide symptomatic relief for some patients [ 5 , 23 ]. Endometriosis lesions have more than a 100-fold increase in estrogen receptor (ER) β expression compared to the eutopic endometrium. Recent GWAS analysis identified loci associated with endometriosis risk, all of which function in sex steroid hormone pathways ( FN1 , CCDC170 , ESR1 , SYNE1 , and FSHB )[ 95 ]. Exposure to endocrine disrupting chemicals (EDCs) in utero or early in life collectively impact the immune system influencing female reproductive health and the development of endometriosis [ 96 , 97 ]. Additionally, gut microbiota have the capacity to influence distant organs and their associated biological pathways through both the neurologic, immune, and endocrine systems [ 98 ]. Not only is the collective gastrointestinal microbiome capable of metabolizing and modulating the circulating estrogens, sometimes referred to as the estrobolome, but gut dysbiosis may contribute to development and perpetuation of endometriosis symptoms by altering the immune environment in the reproductive tract and pelvic region [ 99 ]. Cross-sectional observational studies of endometriosis suggest immune differences exist over the female life course. Endometriosis exhibits a more pro-inflammatory molecular profile within the peritoneal cavity during adolescence compared to adulthood, characterized by a significant enrichment and activation of proteins linked to angiogenesis and cell migration [ 100 ], alongside a more pro-invasive pattern of peritoneal cytokines [ 101 ]. An interplay between the endocrine system and the immune system that is necessary for the development of endometriosis likely begins during lesion inception and may fluctuate over the life course, although the sequence and timing of these alterations remains unclear. Importantly, elevated levels of estradiol (E2), derived from both local and systemic synthesis, serve as key drivers of lesion growth through immune-related mechanisms, as illustrated in Figure 2 . E2 produced within lesions contributes to lesion growth via immune-related mechanisms, including inhibition of tumor necrosis factor (TNF)-α-induced apoptosis, increasing IL-1β levels, and promoting cell adhesion and proliferation [ 22 , 102 ]. Endometriosis lesions exhibit an increased expression of aromatase, an enzyme responsible for converting androgens into estrogens [ 103 ]. Notably, prostaglandin E2 (PGE2), a well-known mediator of inflammation and pain, induces aromatase activity and local E2 production in endometriosis. In turn, E2 promotes the activity of cyclo-oxygenase-2, amplifying the synthesis of PGE2 and other inflammatory mediators creating a positive feedback loop that perpetuates the survival and growth of endometriosis [ 21 , 104 , 105 ]. Estradiol and ER activity are found to have dose- and context-dependent effects on the development of myeloid cells and the activation of pro-inflammatory pathways [ 106 ]. The hyper-estrogenic microenvironment and changes in ER expression in endometriosis lesions and endometrium may contribute to abnormal progesterone signaling, known as “progesterone resistance” that is seen within endometriosis and contributes to the proinflammatory environment [ 107 , 108 ]. Beyond its role within the lesions, E2 is key contributor to the complex network of neuroendocrine mediators that regulate metabolism, systemic inflammation, and pain sensitivity [ 109 ]. Estrogens play a role in classical receptor-mediated, non-classical, and non-ligand-mediated genomic (nuclear) and non-genomic (extranuclear) pathways to regulate gene expression, protein modifications, and signaling, influencing the functions of both B and T cells [ 110 ]. Stimulated by this immunomodulatory imbalance, hormone-sensitive endometrial cells may develop autonomic and sensory innervation via a neurovascular bundle which, in turn, contributes to neuroinflammatory endometriosis-associated chronic pelvic pain (endo-CPP) [ 111 – 113 ]. The complex and reciprocal interplay between estrogen signaling and both innate and adaptive immune systems may, in part, explain the association seen between endometriosis, other inflammatory conditions, and autoimmune diseases.

Endometriosis remains a chronic and debilitating disease with massive global impact, and healthcare costs. Endometriosis demonstrates mechanistic overlap with autoimmune conditions, and inflammatory pathways play important roles in inception and perpetuation of lesions. Furthermore, similar to autoimmune diseases, it is increasingly clear that endometriosis is a systemic disease, with impact well beyond the endometrium. While significant progress has been made in understanding the immunopathogenesis of endometriosis, more research is needed. In particular, there is a need to better understand the fundamental immune dysfunction associated with the pathogenesis of endometriosis to identify potential new strategies for prevention, diagnosis, and therapeutic intervention. Understanding interactions between the intestinal tract or vaginal microbiome and endometriosis may provide valuable information towards this end. The identification of actionable biomarkers and non-invasive approaches to diagnose women at risk or with disease represents an urgent unmet need in endometriosis. While IL-6 serum levels and anti-endometrial antibodies have been proposed as diagnostic markers for endometriosis, they do not have sufficient reliability to be used in the clinical setting [ 144 ]. A miRNA salivary signature developed using a combination of next-generation sequencing (NGS) and artificial intelligence (AI) was reported as a potential novel, diagnostic tool for endometriosis [ 145 , 146 ]. Various factors known to influence miRNA dysregulation, particularly exogenous hormones and their downstream effects need to be considered before diagnostic biomarkers based on miRNA [ 147 ]. Further, before miRNA can be accepted as clinically reliable test, this technology will require additional validation in larger and diverse populations. Subgroup characterization has described important associations between genotypes and disease phenotypes [ 148 ]. Disease heterogeneity in endometriosis poses a significant challenge, and better phenotyping that includes immune profiles will likely help stratify subgroups of disease and may be beneficial as new therapeutic interventions move into clinical trials. Promising therapeutic management strategies such as replenishing glutathione with N-acetylcysteine [ 149 ] and repurposed drugs with efficacy in autoimmune diseases such as direct mTOR blockade [ 150 , 151 ] may be beneficial in the treatment of endometriosis [ 152 , 153 ]; however, the short and long-term safety of these approaches is unknown and merits further study. Advanced bioinformatics using multivariate analysis of genotypes into subgroups of multiple single nucleotide polymorphisms (SNPs), have defined a genetic interplay between the epigenetic changes of DNA methylation and associated endometriosis disease risk as well as endometrial function, and between endometriosis and inflammatory co-morbidities [ 154 , 155 ]. Recent advancements in multi-omics technology and single-cell analyses have introduced a variety of potential biomarkers, predominantly centered around pro-inflammatory and immune-dysregulated pathways within endometriosis lesions [ 18 , 156 , 157 ]. Preliminary studies characterizing immune features and endometrial cells in menstrual effluent from women with endometriosis offers a novel, noninvasive tool in symptomatic patients [ 28 – 30 , 158 ]. While these immunophenotypes have not yet moved into the diagnostic arena, they do show promise and lend further evidence to the role of the immunome in endometriosis. As the research arena in the field of endometriosis continues to evolve, use of “Novel Alternative Methods” (NAMs) such as organoids and micro-physiologic systems (MPS) will likely provide a complementary approach to traditional animal models [ 159 ]. The design and use of MPS for chronic inflammatory diseases is still evolving, and in vitro tools for sexually dimorphic immunologically competent MPS are still evolving. However, supporting the use of NAMs and other models for endometriosis research is important for advancing the science of endometriosis research, and may provide unique opportunities to accelerate precision therapies for people with endometriosis.

Endometriosis is a female-specific, chronic inflammatory condition in which endometrial-like tissue grows ectopically, most frequently on peritoneal surfaces of the pelvis or the ovaries, at times forming deep lesions usually in the ovaries (endometriomas) or in the retrovaginal septum (nodules in the cul de sac), but can be extrapelvic [ 1 – 3 ]. The condition affects up to 10% of premenopausal women and individuals with a uterus and is estimated to effect approximately 190 million people worldwide [ 1 ]. Common symptoms of endometriosis include dysmenorrhea, pelvic and other types of pain, and infertility. Although up to 20–25% of those affected with endometriosis are asymptomatic, in women with symptomatic pelvic pain the estimated prevalence of endometriosis is as high as 50% [ 4 ]. The gold standard for diagnosis of endometriosis is direct visualization, which requires surgical intervention, typically performed by laparoscopy. Surgery carries increased morbidity and costs, and a lack of reliable or accurate non-invasive techniques to detect endometriosis ultimately contributes to delays in diagnosis, especially among those with limited access to complex gynecologic care and surgery [ 1 , 3 , 5 ]. A definitive diagnosis of endometriosis has been reported to take as long as 11 years following the onset of symptoms [ 6 ]. Yet, the estimated costs associated with endometriosis are similar to those of other chronic conditions such as type II diabetes, suggesting that the economic burden alone should render endometriosis a high priority disease for health care and further study [ 7 , 8 ]. Therapies for endometriosis are also limited. Pain is often managed with non-steroidal anti-inflammatory medications. Hormonal therapies may also be useful for the management of endometriosis-associated pain [ 3 , 5 ]. However, medical management only provides symptomatic pain relief and lesions are not resolved by medical interventions [ 3 ]. Surgery, particularly for resection of deep endometriotic lesions, can be therapeutic; however, even following initial improvement in pain, 30% of women have recurrent pain within a year [ 1 , 9 , 10 ]. Infertility is another well recognized complication of endometriosis, and its mechanisms may be multifactorial. While tubal and ovarian integrity may be compromised by endometriosis deposits and fibrosis, there is also evidence for immunologic mechanisms impeding fertilization and implantation [ 11 – 14 ]. Assisted reproduction is an effective strategy for endometriosis-associated infertility, particularly if tubal function and patency have been compromised by scarring or strictures. However, a better understanding of the mechanisms driving infertility in women with endometriosis could provide additional, and potentially lower morbidity interventions [ 5 ]. Epidemiology studies show that the natural history of endometriosis is influenced by multiple genetic, epigenetic, endocrine, environmental, and lifestyle factors; however, it is increasingly apparent that chronic and systemic inflammation is a necessary component of lesion formation and progression. Longitudinal clinical data repositories, including the Nurses’ Health Study, have shown that women with endometriosis have higher rates of other immunologic conditions, including autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis [ 15 ]. An improved understanding of the critical role of immune dysfunction in the development, progression, and outcomes from endometriosis will be crucial to provide important insights into disease pathogenesis and ultimately may identify new therapeutic targets for this historically understudied disease.

The immune-related alterations in endometriosis are similar to those seen in autoimmune diseases, and this similarity supports a shared pathogenesis between endometriosis and autoimmune diseases. In addition to the localized inflammatory response to endometriosis implants, people with endometriosis exhibit systemic immune dysregulation and have increased risk of immune-related comorbidities including autoimmune diseases, chronic infections and long COVID [ 133 – 136 ]. The relative timing of immune-related and autoimmune conditions in relation to the history of endometriosis is hard to ascertain, despite the strong associations, due to the long lead time to diagnosis for both autoimmune diseases and endometriosis. Data from large cohorts show a high frequency of co-occurrence of autoimmune diseases and endometriosis [ 15 , 134 , 137 ]. However, it is not known whether endometriosis drives autoimmune disease, or whether the autoimmune phenotype contributes to development of endometriosis. In general terms, the combination of inflammation, hypoxia, mitochondrial dysfunction and oxidative environments, which all are key components of endometriosis, are also pivotal in the development of autoimmunity [ 77 ]. The ectopic endometrial tissue, which cyclically bleeds, generates a proinflammatory environment with high potential to escalate autoimmunity through the generation of dead cells and nucleic acid debris, and neoantigens. Failure of innate immune cells to effectively remove self-antigens contributes to activation of adaptive immune cells against neoantigens escaping tolerance induction mechanisms [ 138 , 139 ]. Autoimmunity and endometriosis have been shown to have an additive negative impact on endometrium–embryo crosstalk during implantation. Individuals with endometriosis and concomitant autoimmunity exhibit lower embryo cleavage and implantation rates compared to those affected by endometriosis alone [ 14 ]. Other immune dysregulated mechanisms seen in both endometriosis and autoimmune diseases include autoantibodies and higher levels of pro-inflammatory cytokines in follicular fluid that impair oocyte maturation and embryo development [ 140 – 142 ]. Furthermore, higher levels of pro-inflammatory cytokines in the uterine microenvironment, altered activity of uterine immune cells, and impaired adhesion molecule expression may affect endometrial receptivity [ 12 , 143 ].

While multiple hypotheses exist for the pathogenesis of endometriosis, no single explanation accurately accounts for the multiple, and varied clinical presentations which include disseminated thoracic lesions leading to catamenial pneumothorax, and the rare occurrence of endometriosis in men exposed to high levels of estrogens [ 16 , 17 ]. Recent findings that endometrium and pelvic disease epithelial compartments share identical somatic mutations strongly support the endometrium as a major origin of pelvic disease [ 18 ]. Consideration of lesion type and molecular characteristics alongside the spectrum of possible symptoms and systemic comorbidities may provide insight into endometriosis phenotypes as shown in Table 1 . A notable common theme of all current hypotheses, however, is that an impaired immune system appears to play a critical role in development and perpetuation of endometriosis lesions. Retrograde menstruation, the reverse flow of menstrual blood through the fallopian tubes into the pelvic cavity is a common feature of endometriosis, and the higher incidence of endometriosis observed in those with outflow obstruction is often cited as evidence for retrograde menstruation playing a causal role in endometriosis [ 1 , 19 , 20 ]. However, nearly all menstruation is associated with some retrograde component, suggesting that retrograde menstruation alone cannot fully explain the development of endometriosis and additional factors contribute to endometrial lesion implantation and persistence [ 2 , 3 , 21 – 23 ]. A proinflammatory and hypoxic environment in the peritoneum is needed to promote ectopic implantation, proliferation, and these factors further contribute to induction of angiogenesis in endometrial lesions [ 24 , 25 ]. Factors within menstrual blood that promote inflammation and inhibit apoptosis may also contribute to endometrial cell survival and attachment [ 26 , 27 ]. Menstrual effluent-derived stromal fibroblast cells (ME-SFCs) from females with endometriosis show an endometriosis-like phenotype characterized by a decidualization defect, enhanced cell migration, and enhanced cell adherence compared with ME-SFCs from controls without endometriosis. This endometriosis-like cell phenotype can be created in ME-SFCs from healthy controls without endometriosis that are co-cultured with tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [ 28 , 29 ] Further, in-depth immune cell analysis of menstrual effluent from women with endometriosis has provided insights into how retrograde menses evades the immune system through lower Th17 axis’ activity, fewer macrophages, and lower TGF- α levels compared to that found in healthy donors [ 30 ]. Altered uterine contractility may be an additional mechanical factor promoting retrograde menses that contributes to endometriosis and its associated symptoms [ 31 ]. This abnormal contractility likely extends beyond the menstrual phase and may be driven by a complex interplay of hormonal, inflammatory, and mechanical signals [ 32 ]. Signaling pathways, such as Toll-like receptor 4 (TLR4) and Mitogen-Activated Protein Kinase/Nuclear Factor kappa-light-chain-enhancer of activated B cells (MAPK/NF-κB), are likely upstream inflammatory regulators of this process [ 33 ]. Additional evidence on the interplay between immune dysregulation and abnormal uterine contractility comes from studies conducted in nonpregnant murine models. Intraperitoneal injections of Lipopolysaccharide (LPS) in mice induce uterine myometrial dysfunction and atony [ 34 ], potentially by influencing the activity of large-conductance, voltage-gated, calcium (Ca2+)-activated potassium channels (BKCa) in the myometrium [ 35 ]. Local implantation theories do not adequately account for the formation of extra-pelvic endometrial lesions. Escape of menstrual cells via the venous or lymphatic circulation is postulated to enhance defective immune surveillance [ 20 , 36 ]. Coelomic metaplasia or transformation of peritoneal cells into endometrial stroma and glands has also been promoted as another explanation for the development of endometriosis [ 36 , 37 ]. However, analysis of patients with Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome has sown that endometriosis typically only develops in patients with uterine or endometrial remnants present, underscoring the implantation hypothesis [ 37 ]. Similarly, differentiation of endometrial-derived or bone-marrow derived stem cells into endometrial stroma and glands has been suggested as a putative method for the development of endometriosis [ 21 , 38 ]. These differentiation theories, likely depend on hormonal or immunologic triggers, but as of yet the exact mechanisms of these transformations remain poorly elucidated [ 36 ].

Although endometriosis is itself not a malignant lesion, an association between endometriosis and risk of subsequent development of ovarian cancer has been well described and is likely to involve inflammatory pathways [ 114 , 115 ]. Endometriosis associated ovarian cancer (EAOC) is defined by the presence of ovarian or pelvic endometriosis at the time of diagnosis or pathologic evidence of malignant transformation [ 116 , 117 ]. Although only approximately 1% of patients with endometriosis later develop ovarian cancer, up to 15% of women with ovarian cancer have been previously diagnosed with endometriosis, with the risk highest among patients with endometriosis associated with endometriomas, deep lesions or sub-fertility [ 117 – 123 ]. Type I or low-grade malignancies, endometrioid or clear cell ovarian cancers are the histotypes most commonly associated with endometriosis [ 119 , 124 ]. Immune dysregulation likely plays a role in malignant transformation of endometriosis [ 66 , 117 , 125 , 126 ]. Chronic inflammation around endometriotic lesions can result in reduced immune surveillance and subsequent inhibition of apoptosis [ 66 , 125 ]. NF-κB which is activated in endometriosis participates in a multitude of cancer-promoting events including angiogenesis, proliferation, and metastasis [ 21 , 127 ]. Deep endometriotic lesions have been shown to harbor somatic cancer driver mutations such as ARID1A, PIK3CA, and KRAS that are common in ovarian clear-cell and endometrioid carcinomas implicating their role in the transition from endometriosis to EAOC [ 1 , 128 , 129 ]. Alterations in ARID1A , a core member of the BRG/BRM-associated chromatin remodeling complex, often shared between endometriotic and adjacent malignant lesions, are associated with impairments in IFN gene expression, decreased T-cell function, and resultant immune evasion [ 126 ]. Genomic profiling of EAOC demonstrates that approximately one-third of patients with endometriosis harbor cancer-like immune signatures with significant upregulation of complement pathways [ 130 ]. Complement proteins have been implicated in a variety of mechanisms that promote carcinogenesis in the setting of inflammation including promotion of cellular proliferation, angiogenesis, and immune escape [ 131 ]. Once cancer develops, however, immune activation may well contribute to the improved prognosis for patients with EAOC [ 132 ]. More research is urgently needed into the complex interplay of endometriosis, autoimmunity, and malignant transformation.