Immune Suppression and Somatic Mutation in Endometriosis – An Opportunity for Personalized Immunotherapy

Endometriosis is a chronic, inflammatory condition affecting around 10% of reproductive-age women, characterized by the presence of endometrial-like tissue outside of the uterus. The effects of endometriosis include chronic pelvic pain, menorrhagia and infertility. Despite its prevalence and impact, current therapies remain limited in efficacy and scope. Recent insights into the immunological landscape of endometriosis along with the discovery of common somatic mutations open the door to new ways of thinking about therapies for endometriosis. Individual endometrial glands have been shown to carry distinct cancer-associated somatic mutations, suggesting a mosaic architecture. Clonal selection during retrograde dissemination and lesion establishment is evident such that genetic and epigenetic alterations appear to confer survival advantages. Immune suppression is another characteristic of the endometriotic environment, with evidence including observations of elevated checkpoint molecules in lesions. Here, we propose a future therapeutic framework based on checkpoint inhibition in combination with personalized vaccination targeting patient-specific neoantigens. This perspective integrates immunological, molecular, and clinical insights to propose a novel therapeutic direction. Importantly, the therapeutic framework described herein should be regarded as a hypothesis-generating perspective rather than a clinically validated treatment strategy. While evidence supports immune dysregulation and recurrent somatic mutation in endometriosis, substantial biological, translational and clinical uncertainties remain before mutation-directed immunotherapy could be considered feasible in clinical practice.

checkpoint inhibition, endometriosis, immune suppression, immunotherapy, mRNA vaccine, neoantigens, personalized vaccine

Endometriosis is a debilitating condition marked by the growth of endometrial-like tissue outside of the uterine cavity, commonly affecting the peritoneum, ovaries, and other pelvic structures.1 Fibrosis, angiogenesis and inflammation are among the inherent characteristics of ectopic lesions.2 Chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility are among common symptoms, with significant impacts on quality of life. The global burden is substantial, affecting approximately 200 million women and girls, with delayed diagnosis and limited treatment options contributing to prolonged suffering. Current diagnostic approaches rely heavily on laparoscopy, often years after the onset of symptoms. Therapeutic strategies typically involve hormonal suppression and surgical excision and although a diverse range of alternative approaches have been considered, recurrence rates remain high, and side effects are common.1,3,4 Costs associated with treatment and lost productivity are considerable but despite its prevalence, endometriosis has been under-researched relative to its impact.5 Recent molecular and immunological insights suggest that a re-evaluation of the pathogenesis of endometriosis may unlock new therapeutic avenues - in particular, the presence of immune dysregulation6,7 and somatic mutations.8 Endometriosis is increasingly recognized as a heterogeneous disorder comprising three principal anatomical subtypes: superficial peritoneal endometriosis, ovarian endometriosis, and deep endometriosis. These forms differ in anatomical location, fibrosis, inflammatory profiles, symptom burden, recurrence risk, and molecular characteristics. Disease severity is commonly classified using the revised American Society for Reproductive Medicine staging system (Stages I–IV). However, symptoms and infertility correlate poorly with stage, suggesting biological characteristics may be as important as anatomical extent. While immunotherapy has been proposed previously as a broad potential treatment strategy for endometriosis, most approaches to date have focused on immune modulation - such as targeting inflammatory cytokines, macrophage polarization, or T-cell activation—without accounting for underlying genetic heterogeneity.4 These strategies do not explicitly focus on the presence of somatic mutations in endometriotic lesions that could yield neoantigens capable of eliciting a targeted immune response. In contrast, this perspective piece introduces the concept of leveraging personalized vaccination against patient-specific endometriotic somatic changes to enhance the efficacy of immune checkpoint inhibition and other immune modulators (Figure 1). This approach aligns with emerging paradigms in cancer immunotherapy and may offer a precise and durable therapeutic option. | Figure 1 Schematic workflow of putative immune checkpoint inhibition combined with personalized neoantigen mRNA vaccination. | Literature Review Approach This article was developed as a narrative review and perspective. Relevant literature was identified primarily through PubMed and associated citation tracking, with a focus on studies relating to endometriosis immunology, immune checkpoint signalling, somatic mutation, clonal evolution, neoantigen biology and personalized immunotherapy. Literature identification was iterative, incorporating both primary research articles and review articles, with additional studies identified through reference lists and emerging concepts relevant to the proposed therapeutic framework. The objective was not to perform a systematic review but rather to synthesise current knowledge and explore a hypothesis-generating conceptual model. Immune Privilege in the Eutopic Endometrium The eutopic endometrium is a dynamic immunological niche that undergoes cyclical remodeling under the influence of ovarian steroid hormones, primarily estradiol and progesterone.9 These hormones orchestrate a finely tuned balance between immune tolerance - essential for embryo implantation - and immune surveillance to prevent infection and malignancy. During the secretory phase of the menstrual cycle, after ovulation, rising progesterone levels induce a tolerogenic shift in the endometrial microenvironment.10 Indoleamine 2,3-dioxygenase (IDO) catabolizes tryptophan into kynurenine, which exerts immunosuppressive effects.11 Even prior to pregnancy, decidual stromal cells, differentiated under progesterone induction, express this enzyme and levels of expression correlate with levels of Foxp3+ regulatory T cells (Tregs)12 which, in turn, suppress effector immune cell responses.13 Prostaglandin E2 (PGE2) is also produced in the human uterus prior to pregnancy. In the endometrium, PGE2 is the predominant prostaglandin and is involved in preparing the uterine lining for potential implantation, promoting vascular permeability, angiogenesis, and decidualization of endometrial stromal cells. PGE2 also modulates immune tolerance in the uterus to create a receptive environment for the embryo.14 PGE2 promotes T helper 2 cell (Th2), T helper 17 cell (Th17) and regulatory T cell (Treg) responses and modulates chemokine production to inhibit the attraction of pro-inflammatory cells whilst increasing the local accumulation of Tregs and myeloid-derived suppressor cells.15,16 It suppresses the ability of dendritic cells to attract naïve, memory- and effector T cells. PGE2 also suppresses effector functions of macrophages and neutrophils as well as Th1-, CTL- and NK cell-mediated type-1 immunity. Uterine NK (uNK) cells are the most abundant immune cells in the endometrium, adopting a CD56brightCD16− phenotype.17,18 While a role in immune tolerance is more pronounced during pregnancy, pre-pregnancy uNK cells exhibit features that support a tolerogenic environment, including reduced cytotoxic receptor expression, limited activation of cytolytic pathways and the secretion of regulatory cytokines that modulate other immune cells.19 uNK cells are predominantly poorly cytotoxic and instead play a role in maintaining immune tolerance in preparation for potential implantation as well as supporting vascular remodelling and endometrial shedding and regeneration. It has been reported that IDO expression is elevated in the eutopic endometrium (as well as ectopic) in individuals with endometriosis.11 Similarly, PGE2 levels have been observed to be higher in the menstrual fluid of women with endometriosis than unaffected women.20 Together, these factors likely heighten an already preconditioned immunosuppressive environment and facilitate the survival of aberrant endometrial cells. Somatic Mutations in the Eutopic Endometrium Recent studies have revealed that the eutopic endometrium is not genetically uniform but instead comprises a mosaic of clonal epithelial populations harboring distinct somatic mutations including those in cancer-associated genes. Deep sequencing and laser microdissection analyses identified alterations in genes such as KRAS, PIK3CA, ARID1A, PPP2R1A, and PTEN within individual endometrial glands.8,21 Suda et al sequenced 109 single endometrial glands and found that each gland carried distinct somatic mutations. Focused immunohistochemistry (IHC)-based screens have detected expression loss of PTEN and PAX2 in normal endometrium.21,22 Mutant allele frequency (MAF) analyses have revealed that some mutations are present at relatively high frequencies, indicating clonal expansion. Such alterations are typically confined to the epithelial compartment and occur at low allele frequencies in eutopic tissue, suggesting early clonal events.8 While these mutations do not necessarily indicate malignancy, they may confer survival advantages, such as resistance to apoptosis, enhanced proliferative capacity, and adaptation to inflammatory or hypoxic niches. This clonal diversity might serve as a reservoir for mutant cells with increased potential to survive at sites outside of the uterus. Establishment of Ectopic Endometrium-Like Lesions The prevailing theory of retrograde menstruation posits that endometrial fragments reflux through the fallopian tubes into the peritoneal cavity.23 Other theories for the formation of lesions include stem cells, epithelial-mesenchymal transition (EMT), and coelomic metaplasia. While endometriosis is generally recognized as a benign condition, ectopic lesions can exhibit features reminiscent of malignancy, including resistance to apoptosis, angiogenesis, local invasion, the ability to disseminate, and immune suppression.24 It has also been proposed that endometriosis comprises a heterogeneous collection of pathologies, which may explain divergent presentations.24 Interrelated functional pathways that underlie properties of ectopic lesions include: altered hormone signalling characterized by exaggerated estrogenic drive and impaired progesterone receptor signalling; persistent proinflammatory signalling and immune cell dysregulation; oxidative stress responses; evasion of apoptosis; angiogenesis; and the promotion of tissue invasion, migration and EMT.24 Emerging evidence suggests that both somatic mutations and epigenetic alterations contribute to the endometriotic phenotype.8,25 Endometriosis has been shown to be polyepigenetic, involving DNA methylation changes across multiple genes and pathways. Altered methylation in ectopic lesions has been observed for genes involved in cancer-related processes, including cell proliferation and differentiation (eg, PI3K-Akt, Wnt signalling), cell division, cell adhesion and communication, hormonal response, apoptosis and immunity.25 Some genomic regions have also been shown to be differentially methylated in eutopic endometrial tissue of endometriosis patients in comparison to that of healthy controls.25 To survive in hypoxic, oxidative environments, endometriotic lesions reprogram metabolism, adopting aerobic glycolysis (Warburg effect), and exhibit altered mitochondrial dynamics among other mechanisms.26–28 Somatic Mutations in Ectopic Endometriotic Lesions In their important work, Suda et al showed that mutated clones from the eutopic endometrium can seed ectopic sites and undergo further clonal dissemination and selection. This process mirrors early oncogenesis and may be driven by selective pressures in the ectopic microenvironment, including immune suppression and hypoxia. Epithelial clones appear to be the primary drivers of lesion formation - stromal cells consistently lacked these mutations. Following whole-exome sequencing in 13 endometriotic and 11 normal uterine endometrial epithelial samples along with matched normal blood samples, a total of 4192 somatic mutations were observed. The median number of exonic somatic mutations was 128, with a range from 72 to 536. Other groups have also examined somatic mutations in endometriosis spanning methodologies from cytogenetics to massively parallel sequencing and finding mutation events ranging from chromosome imbalances to recurrent somatic cancer driver mutations, including in KRAS, PIK3CA, ARID1A and PPP2R1A.21 Mutations are often accompanied by allelic imbalances or copy number alterations, suggesting that they confer survival and proliferative advantages at ectopic sites. Mutant allele frequency (MAF) analyses consistently show higher MAFs in ectopic lesions compared to matched eutopic tissue, indicating clonal expansion under selective pressures. Notably, somatic mutations in endometriosis are not randomly distributed with respect to site. For example, ovarian endometriomas exhibit higher frequencies of ARID1A and PIK3CA mutations, which are also implicated in endometriosis-associated ovarian cancers. This might suggest a continuum between benign and malignant phenotypes, with mutation burden and clonal architecture potentially influencing cancer risk. Moreover, the presence of identical mutations in both eutopic and ectopic tissues supports a model of early mutational events in the uterus followed by selective dissemination and expansion at ectopic sites.8,21 A recent longitudinal IHC-based study showed that PTEN and ARID1A (both commonly lost in endometrial cancer) loss were very frequent in endometriosis (68.3% and 24.6%, respectively in the studied cohort at the participant level)29 and PTEN loss was significantly associated with more severe anatomic subtypes. Together, these findings imply that somatic mutations and epigenetic alterations are not incidental but may be necessary for the establishment, maintenance, and progression of ectopic lesions. Their enrichment in specific anatomical sites and correlation with disease severity and cancer risk underscore their likely clinical relevance. Although recurrent somatic mutations are now well established in endometriosis, the extent to which these mutations produce clinically relevant neoantigens remains unknown. The presence of a DNA mutation alone is insufficient to generate an immunogenic target. Mutated genes must also be expressed, processed, transported, presented by patient-specific MHC molecules and recognised by T-cell receptors. Consequently, only a subset of somatic mutations, and perhaps patients, would be expected to generate therapeutically actionable neoantigens. Important uncertainties remain regarding lesion clonality and dissemination. While shared mutations between eutopic endometrium and ectopic lesions support a clonal dissemination model, the extent of inter-lesion heterogeneity, polyclonal seeding, lesion-specific evolutionary divergence and recurrence dynamics remains poorly characterized. Challenges associated with resolving these relationships include the selection strategy for lesion region sampling and the high depth of sequencing and appropriate bioinformatic processing required to detect sub-clonal somatic mutations with high sensitivity and accuracy. Epithelial-Origin Cells in Endometriotic Lesions Although endometriosis is classically defined as involving ectopic lesions harbouring endometrioid-type glands and endometrioid-type stroma, the disease actually comprises a spectrum of different phenotypes with lesions exhibiting varying degrees of epithelial and stromal composition.30–32 It has been stated, however, that in common to all variants is the presence of epithelial cells, stromal cells and an active neo-angiogenesis at the point of initiation.31 Boyle and McCluggan reported stromal endometriosis in 44.9% of biopsies, wherein epithelial gland structures were not visible. Often, such biopsies also displayed typical endometriosis. However, in 6.6% of biopsies they reported stromal endometriosis in the absence of typical endometriosis.30 While stromal endometriosis was defined by the lack of epithelial glands, it is not clear to what extent stromal lesions harboured epithelial cells or cells of epithelial origin. Single-cell RNA sequencing analysis indicates that samples assigned as non-endometriotic by pathology review can actually be endometriotic - characterised by epithelial cells, along with stroma and the activation of stress response and heme degradation pathways in mesothelial cells.33 Related to this, and the challenges of identifying epithelial cells via standard pathology, EMT is reported to be a crucial component of the fibrotic process observed in endometriosis and that this likely occurs after the formation of lesions as part of their evolution.2,34–37 This process would be expected to result in epithelial-origin lesion cells that adopt different phenotypes with important roles in lesion maintenance. Lesion stroma are predominantly composed of cells with different origins to the epithelia and exhibit somatic mutations with relatively low clonality. However, even in the setting in which glandular structures are clearly distinguishable and where we might not expect EMT to have been extensive, tantalising evidence from digital droplet PCR experiments suggests that small numbers of cells of epithelial origin are detectable in stromal regions of lesions.38,39 Fonseca et al reported an enrichment in endometriosis tissues for KRT10- and ACTA2-expressing cells that appear to be less differentiated subsets of endometrial-type stroma. Since KRT10 and ACTA2 are recognised markers for epithelial cells and mesenchymal cells, respectively, it seems likely that these represent an EMT process. Future lineage tracing work will be needed to resolve the extent of epithelial-origin cells across a range of lesion types and to examine their requirement for lesion persistence, invasion and spread. It is intriguing to speculate that cells of epithelial origin, including those resulting from EMT and other differentiation processes, remain important components of a broad range of endometriosis lesions, including in stromal endometriosis, influencing their viability and invasive properties. As such, clonal somatic mutations originating in epithelial cells would present as important potential targets for the immune system across a broad variety of endometriotic lesion types. Immunosuppression Associated with Ectopic Endometriosis Lesions Ectopic lesions are characterized by a unique immune microenvironment that suppresses cytotoxic responses and promotes lesion survival.40 Tregs are enriched, secreting IL-10 and TGF-β to inhibit effector T cells. M2 macrophages dominate, producing VEGF and matrix metalloproteinases that support angiogenesis and tissue remodeling. Dendritic cells in lesions often exhibit a tolerogenic phenotype, failing to activate T cells effectively. Concentrations of PGE2 in peritoneal fluid are higher in women suffering from endometriosis than disease-free women.41 Similarly, IDO expression is upregulated in ectopic endometriotic stromal cells, with implications for the local immune environment.42 Upregulation of non-classical MHC molecules, particularly HLA-G and HLA-E have been reported in endometriotic lesions - these interact with inhibitory NK cell receptors, leading to suppression of NK cell cytotoxicity.40 Checkpoint pathways such as PD-1/PD-L1, CTLA-4/CD80/CD86, TIM-3/Gal-9 and CD47/SIRPα have been documented to be dysregulated in endometriosis,40,43–45 mirroring tumour microenvironments. Immunosuppression via altered checkpoint signalling facilitates mutated endometriotic epithelial cells to evade clearance and persist. Autoimmunity The presence of autoantibodies against endometrial, endothelial, and oxidative stress markers has been reported in endometriosis-affected women.46–52 However, the pathogenic role of these antibodies remains debated. Mechanistically, chronic inflammation and tissue damage could expose neoantigens, triggering autoantibody production. Alternatively, somatic mutations might generate novel epitopes that break immune tolerance. The presence of autoantibodies may reflect an epiphenomenon in endometriosis rather than a causal mechanism. Nonetheless, the autoimmune features of endometriosis must be considered when designing immunotherapies, as immune activation could exacerbate self-reactivity. Immunotherapy and Endometriosis Previous authors have presented a compelling case for repositioning endometriosis as an immune-mediated disorder, highlighting the potential of immunotherapy to address the chronic inflammation and immune dysfunction that underpin disease persistence. Wide-ranging approaches to immunotherapy for endometriosis have been proposed.4,6,7,53 For example, recombinant human TNF binding protein (r-hTBP1), as a soluble form of TNF receptor type 1, has been reported to reduce the size of endometriotic implants in rats.54 This agent was also shown to reduce the scale and severity of lesions in a baboon model of endometriosis.55 In a mouse model of endometriosis, peritoneal injection of IL-12 appeared to enhance the cytotoxicity of NK cells and inhibit endometriosis-like lesion development.56 Similarly, IL-37 – which influences dendritic cells via a number of mechanisms, including enhancement of their antigen presentation and their inducement of an increased Th1/Th2 ratio - has been shown to inhibit the development of endometriosis-like lesions in mice when administered intraperitoneally.57 Administration of IFN-α-2b was shown to reduce the size of endometriotic implants significantly in rats,58 whereas blocking local IL-10 activity using monoclonal antibody can suppress endometriotic lesion growth in mice.59 Other cytokines or cytokine receptors have also been targeted by monoclonal antibodies with apparent beneficial effects in animal models of endometriosis.4,60–62 Treatment with the immunomodulatory vitamin D3 has also been shown to regress endometrial implants in a rat model of endometriosis.63 Targeting of immune checkpoint signalling has been observed to be a very promising treatment in rodent models of endometriosis. Regarding immune checkpoint signalling blockade, Liu et al64 demonstrated that anti-CTLA4 therapy in mice can reduce lesion size and modulate Treg populations. Similarly, Mamillapalli et al44 reported that anti-PD-L1 antibody treatment markedly decreased lesion volumes compared to an isotype control. The use of vaccines as immunomodulators has also been investigated in endometriosis research. The Bacillus Calmette-Guerin (BCG) vaccine, designed to target Mycobacteria, has previously been shown to induce xenoprotection against infection, cancer and autoimmunity. In rat models of endometriosis, BCG was reported to inhibit the implantation of endometriosis and enhance peritoneal immune surveillance65 – this appeared to involve the activation of cytotoxic NK cells, an increased polarization to M1 macrophages and the promotion of M2 macrophages to secrete less of the immune-inhibitory IL-10. In a promising related approach, in a preliminary human trial, the xenogenic “RESAN” agent was reported to yield substantial improvements in 10 endometriosis patients.66 Subsequently, in a rat model, RESAN decreased the rate of induction of endometriosis dramatically.66 RESAN is a complex of molecules extracted from chicken tissues – it contains glycoproteins, peptides and carbohydrate fragments of more than 40 different common tumour antigens. In the context of endometriosis, Szymanowski et al66 suggested that RESAN might be better characterized as an immunomodulator rather than a true vaccine, analogous to DETOX (detoxified Freund’s adjuvant). Indeed, they reflected that we did not know which specific antigens differentiate endometrioma from eutopic endometrium and that, therefore, manufacturing a specific, anti-endometriotic vaccine seemed to be impossible. A Proposal for Endometriosis Therapy: Checkpoint Inhibitors Combined with Personalized Vaccines The findings of elevated checkpoint molecules in endometriotic lesion cells and elevated checkpoint molecules in the serum of endometriosis-affected women support the rationale for using checkpoint inhibitors to restore immune surveillance and the targeting of lesion-forming clones. Checkpoint inhibitors, including anti-PD1 and anti-CTLA4 antibodies, have revolutionized cancer therapy by restoring T-cell function in immunosuppressed environments. Their application in endometriosis is supported by the presence of checkpoint molecules and immunosuppression in ectopic lesions as well as the promising results noted earlier in animal models.44,64 The combination of personalized anti-cancer vaccines with immune checkpoint blockade has shown synergistic benefits in the cancer setting – and RNA-based vaccines, via a variety of delivery modes, have shown particular effectiveness and future promise.67–69 The application of mRNA vaccine platforms allows very flexible and responsive synthesis of epitopes. In a recent melanoma clinical trial, for example, mRNA-4157 combined with pembrolizumab (a monoclonal antibody targeting PD-1) approximately halved the risk of cancer recurrence and/or death at a median follow-up time of 35 months in comparison to the checkpoint inhibitor monotherapy.70,71 Similarly, in a pancreatic cancer clinical trial that combined atezolizumab (anti-PD-L1) and the autogene cevumeran personalized vaccine (mRNA-based delivery of up to 20 neoantigens per patient) along with a four-drug chemotherapy regimen, extremely encouraging results were observed in terms of recurrence-free survival among patients who mounted immunity to the vaccine.72 Abnormal endometriotic tissue could potentially be targeted with greater specificity and effectiveness than existing systemic therapies. However, identical somatic mutations may also be present within subsets of eutopic endometrial glands. Consequently, complete avoidance of effects on normal endometrium cannot currently be assumed – although, early indications are that these might be confined to the single gland level. Here, we propose that, analogous to the cancer setting, patients with endometriosis can benefit from combination therapy that includes immune checkpoint inhibition and personalized vaccination targeting somatic mutations (Figure 1). Such an approach might be bolstered by other immune-modulating agents, including those involved in cytokine signalling, toll-like receptor signalling, and the use of CAR-T cells. This approach would begin with lesion biopsies and deep whole-exome or whole-genome sequencing to identify candidate somatic mutations that might yield targetable neoepitopes. Biopsies could be microdissected to enrich for epithelial tissue or, in the future, enrichment for epithelial-origin cells might involve cell sorting based on markers for epithelial cells or epithelial-origin cells that have undergone EMT. Personalized vaccine designs apply bioinformatic pipelines (eg, facilitated by pVACtools)73 that should consider epitope selection, expression, immunogenicity, and avoidance of cross-reactivity with self-antigens, leveraging machine learning algorithms to predict MHCI and MHCII binding and antigen presentation. Sequencing data from biopsies can be integrated with HLA typing to predict patient-specific candidate epitope binding affinities. Predictions of immune response in personalized vaccine regimes will likely be improved further in the future by including computational consideration of T cell receptor (TCR) recognition - as applied in the cross-reactivity (CR) distance model, for example.74,75 The costs associated with personalized vaccine regimens are currently very high – estimated to be over $100,000 per patient in 2025.69 However, as this technology transitions from the boutique clinical trial setting to routine production, these would be expected to reduce by orders of magnitude – presenting a very exciting prospect for the treatment of endometriosis.

and Future Validation Requirements Several important biological and clinical uncertainties should be acknowledged. Although somatic mutations are common in endometriosis, the presence of mutation does not necessarily imply the generation of an immunologically actionable neoantigen. Only a fraction of mutations would be expected to satisfy the expression, processing and presentation requirements outlined earlier, and the initial set of candidate target mutations might be limiting for many patients. This might be countered somewhat by potentially reduced loss of expression and antigen presentation compared with malignancies, however. Our understanding of clonal relationships among eutopic endometrium and ectopic lesions remains incomplete. Safety considerations are likely to be particularly important in endometriosis. Unlike malignancy, endometriosis is a benign disease and therefore acceptable treatment-associated risks are substantially lower. Potential immune-related toxicities or side-effects that may be acceptable in life-threatening cancers would require considerably greater justification in a chronic non-malignant condition. In the case of endometriosis, considerations include fertility, implantation, pregnancy, menstrual physiology and long-term reproductive health. Direct evidence demonstrating naturally presented neoantigens or efficacy of mutation-directed vaccination in endometriosis is currently lacking. Accordingly, the framework proposed here should be regarded as a biologically plausible but unproven therapeutic hypothesis. Future studies should include deep sequencing of multiple lesions and matched eutopic endometrium, lineage mapping, immunopeptidomics, neoantigen-specific T-cell assays, organoid systems, lesion-derived cellular models and humanized animal systems. Ongoing cancer personalized vaccine and immunotherapy trials will also be informative regarding anticipated off-target effects in the endometriosis setting.

Endometriosis is a complex disease with features of immune privilege, somatic genetic and epigenetic alterations, and immune suppression. Frequent somatic mutations may provide future opportunities for personalized immunotherapy, but substantial biological, translational and clinical validation will be required before such approaches can be considered realistic therapeutic options. Future work should focus on defining lesion clonality, validating naturally presented neoantigens, establishing safety boundaries and determining whether lessons from oncology can be translated appropriately to this benign but highly burdensome disease. This framework should therefore be viewed as a hypothesis-generating model intended to stimulate future research rather than an immediately actionable strategy. Generative AI Statement The author(s) declare that no Generative AI was used in the creation of this manuscript. Abbreviations ARID1A, AT-rich interaction domain 1A; BCG, Bacillus Calmette–Guérin; CAR-T, chimeric antigen receptor T cells; CD, cluster of differentiation; CR, cross-reactivity; CTLA-4, cytotoxic lymphocyte-associated protein 4; EMT, epithelial-mesenchymal transition; HLA, human leukocyte antigen; IDO, indoleamine 2,3-dioxygenase; IFN, interferon; IHC, immunohistochemistry; IL, interleukin; KRAS, Kirsten rat sarcoma viral oncogene homolog; MAF, mutant allele frequency; MHC, major histocompatibility complex; PAX2, Paired Box 2; PD-1, programmed cell death protein 1; PD-L, programmed death-ligand; PGE2, prostaglandin E2; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PPP2R1A, Protein Phosphatase 2 Regulatory Subunit A Alpha; PTEN, Phosphatase and Tensin Homolog; TCR, T cell receptor; TGF, transforming growth factor; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; TNF, tumour necrosis factor; Th1/Th2/Th17, T helper cell subsets; Tregs, regulatory T cells; uNK, uterine natural killer cells. Acknowledgments The authors wish to thank The University of Melbourne’s: Melbourne Bioinformatics; Faculty of Medicine, Dentistry and Health Sciences (FMDHS); and the Melbourne Collaborative Infrastructure Program (MCRIP), for ongoing support. Author Contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work. Funding This work was supported by: Melbourne Bioinformatics; MCRIP; FMDHS, The University of Melbourne. No external funding was received for the preparation of this manuscript. Disclosure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Nature. 2022;606:389–395. doi:10.1038/s41586-022-04735-9 © 2026 The Author(s). This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms and incorporate the Creative Commons Attribution - Non Commercial (unported, 4.0) License. By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms. Recommended articles Identification of Lower Grade Glioma Antigens Based on Ferroptosis Status for mRNA Vaccine Development Zhao Z, Xing N, Guo H, Li J, Sun G Pharmacogenomics and Personalized Medicine 2024, 17:105-123 Published Date: 11 April 2024