Immune escape in endometriosis: mechanisms, reprogramming strategies, and precision interventions

Abstract

Background

Endometriosis is a prevalent estrogen-dependent inflammatory disorder that compromises women’s quality of life and fertility through chronic pelvic pain, inflammation, and reproductive dysfunction. Current clinical management remains largely palliative, with high recurrence rates and limited disease-modifying options. Evidence emerging over the past five years supports immune escape as a lesion-centered framework for understanding disease persistence and recurrence, in which ectopic lesions survive within an immune-active but clearance-deficient niche.

Methods

This narrative review synthesizes recent mechanistic and translational evidence on immune escape in endometriosis. We organize the literature into a lesion-centered mechanistic hierarchy encompassing lesion-derived cues, defective phagocytic clearance, impaired cytotoxic surveillance, tolerogenic immune priming, checkpoint-mediated protection, and lesion-supportive inflammatory remodeling. We also evaluate emerging immune-reprogramming strategies, including hormone-sparing immunomodulation, nanotechnology-enabled lesion-targeted delivery, and selected concepts adapted from oncology immunotherapy.

Results

Available studies indicate that lesion-derived inflammatory, metabolic, endocrine, and stromal signals reprogram innate and adaptive immune responses. These changes impair macrophage-mediated clearance, restrain NK-cell and CD8⁺ T-cell cytotoxic functions, alter dendritic-cell-mediated priming and CD4⁺ T-cell regulation, activate inhibitory checkpoint pathways, and redirect inflammation toward angiogenesis, fibrosis, pain sensitization, and local immune tolerance. Together, these processes generate an inflamed yet clearance-deficient niche that may support lesion establishment and persistence. Preclinical immune-reprogramming approaches have shown potential to restore clearance or rebalance pathogenic immune circuits, while nanotechnology-based platforms may improve lesion-local exposure and reduce systemic effects. However, clinical evidence remains limited, and oncology-derived strategies require careful adaptation to the benign, estrogen-dependent, and fertility-relevant context of endometriosis.

Conclusion

A lesion-centered immune-escape framework provides a mechanistic basis for understanding how immune dysfunction contributes to endometriosis persistence and progression. This framework may guide the development of non-hormonal immune-targeted therapies and biomarker-informed patient stratification, although substantial translational validation is still required.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12958-026-01584-3.

Introduction

Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by ectopic endometrial-like lesions, pain, infertility, and frequent recurrence. It affects approximately 10% of women of reproductive age worldwide and is diagnosed in a substantial proportion of women evaluated for infertility [1]. Current management includes analgesics, hormonal therapy, surgery, and assisted reproductive treatment when pregnancy is desired. Hormonal therapies, including combined hormonal contraceptives, progestins, and gonadotropin-releasing hormone agonists or antagonists, are recommended for endometriosis-associated pain, but ovarian suppression is not recommended as a fertility-enhancing treatment in infertile women with endometriosis [2]. Surgery may relieve pain and remove visible lesions, yet recurrence remains a major concern, and surgery for ovarian endometrioma can reduce ovarian reserve, particularly after repeat procedures [2, 3]. Diagnosis is frequently delayed, recurrence is common, and long-term endocrine therapy may be poorly tolerated or unsuitable for women desiring pregnancy [4]. These limitations underscore the need for non-hormonal strategies that target disease-sustaining mechanisms beyond endocrine dependence, including immune-mediated lesion persistence.

Endometriosis is increasingly recognized as a disorder of immune dysregulation, involving altered innate and adaptive immune responses within the peritoneal cavity, eutopic endometrium, and ectopic lesions [5]. In this review, immune escape is used as a more functionally restricted concept within this broader landscape. It refers to a lesion-centered process in which ectopic endometrial tissue persists despite ongoing immune activation, reflecting ineffective immune surveillance, local tolerance, and incomplete clearance [6]. This concept is consistent with broader immune-evasion frameworks [7], but in endometriosis it should be interpreted in the context of a benign, estrogen-dependent, and fertility-relevant inflammatory disease rather than as a direct analogue of malignant immune escape. Accordingly, this review organizes immune escape in endometriosis as a lesion-centered mechanistic hierarchy. We begin by identifying lesion-derived cues that initiate immune-cell reprogramming and then organize the resulting mechanisms into five central immune-escape functions: defective phagocytic clearance, impaired cytotoxic surveillance, tolerogenic immune priming, checkpoint-mediated protection, and lesion-supportive inflammatory remodeling. This framework links established immune abnormalities to the formation of an inflamed yet clearance-deficient niche, thereby providing a mechanistic basis for understanding lesion persistence, pain, infertility, recurrence, and disease heterogeneity.

Advances in mechanistic and translational research have positioned immune reprogramming as a potential non-hormonal therapeutic direction in endometriosis. Representative preclinical studies suggest that macrophage-targeted strategies, including blockade of the CD47–SIRPα “don’t-eat-me” axis [8] or modulation of innate immune memory [9], may enhance ectopic cell clearance and restrain lesion growth. Other experimental approaches, such as Bruton’s tyrosine kinase (BTK) inhibition or indoleamine 2,3-dioxygenase 1 (IDO1) blockade, further support the possibility that shifting suppressive immune programs can reduce lesion burden in model systems [10, 11]. However, these findings remain primarily proof-of-concept. Human evidence is still limited and largely exploratory, with available studies often constrained by small cohorts, short follow-up, heterogeneous endpoints, or biomarker-focused designs that do not necessarily translate into durable clinical benefit. For example, resveratrol has been reported to modulate eutopic endometrial immune-related mediators during the implantation window [12], whereas a randomized double-blind placebo-controlled trial observed only modest pain improvement when resveratrol was added to combined oral contraceptives at the tested regimen [13]. Thus, immune-targeted approaches should currently be regarded as experimental strategies, not clinically established alternatives to standard hormonal or surgical management.

The literature discussed here was identified primarily through PubMed, Web of Science, and Scopus, covering studies published mainly from 2020 to 2025, together with selected earlier landmark reports. Search terms included combinations of “endometriosis”, “immune escape”, “immune dysregulation”, “macrophages”, “natural killer cells”, “T cells”, “B cells”, “dendritic cells”, “neutrophils”, “mast cells”, “immune checkpoints”, “immunotherapy”, and “nanotechnology”. Priority was given to original research articles, clinical studies, systematic reviews, and recent mechanistic or translational studies relevant to immune surveillance, lesion persistence, immune reprogramming, and biomarker development in endometriosis.

Mechanisms of immune escape in endometriosis

Lesion-derived and lesion-associated cues initiate immune-cell reprogramming

Immune escape in endometriosis begins within a lesion-conditioned microenvironment. Ectopic endometrial tissue is exposed to cyclic bleeding, hypoxia, estrogenic signaling, inflammatory mediators, metabolic by-products, extracellular vesicles, and platelet interactions. These cues jointly reshape immune-cell behavior within the peritoneal cavity and lesion niche, converting immune activation into a state that is insufficient to clear ectopic tissue.

Several types of lesion-associated signals contribute to this upstream conditioning. Bleeding-derived heme and iron stress can impair macrophage phagocytosis and efferocytosis, while interleukin-17A (IL-17A, sphingosine-1-phosphate (S1P), and stromal-derived lactate promote lesion-supportive myeloid remodeling [14–17]. Suppressive cytokines in peritoneal fluid, lesion-derived exosomes, platelet coating, and estrogenic signals restrain natural killer (NK)-cell cytotoxicity [18–21]. Local cortisol metabolism, IL-10-rich signals, and angiogenic cues may also affect dendritic cell maturation and antigen-presenting capacity [22–24]. Together, these signals provide the upstream context for the central immune-escape functions discussed below, including defective phagocytic clearance, impaired cytotoxic surveillance, tolerogenic immune priming, checkpoint-mediated protection, and lesion-supportive inflammatory remodeling.

Defective phagocytic clearance and lesion-supportive myeloid remodeling

Failure of macrophage-mediated clearance represents one of the central immune-escape functions in endometriosis (Fig. 1A). Macrophages are abundant in ectopic lesions and peritoneal fluid, where they normally participate in phagocytosis and efferocytosis, two processes required for removing ectopic cells, dead cells, and cellular debris. In endometriosis, however, macrophage phenotypes are reshaped along a functional continuum that links impaired clearance with lesion-supportive remodeling [25].

Fig. 1.

Integrated mechanisms of immune escape in endometriosis. A Defective macrophage-mediated phagocytosis and efferocytosis, together with M2-like remodeling, support lesion survival and tissue remodeling. B NK-cell and CD8⁺ T-cell cytotoxic functions are impaired. C Immature or tolerogenic dendritic cells weaken effective T-cell priming and favor Treg induction and Th17 skewing. D CD47–SIRPα, PD-1–PD-L1, and CTLA-4–B7 checkpoint axes reinforce impaired clearance, cytotoxicity, and T-cell priming. E NETs, mast cell-derived mediators, and regulatory immune cells promote lesion attachment, immune suppression, inflammatory remodeling, and pain sensitization. These modules converge on angiogenesis, fibrosis, pain, and lesion persistence. Created with BioRender.com

Several lesion-associated cues converge on this macrophage-centered escape function. IL-17A promotes M2-like polarization and monocyte recruitment [14], while S1P induces receptor-dependent macrophage outputs, including a cyclooxygenase-2 (COX-2) response, and is associated with expansion of endometriotic-like lesions in vivo [15]. Stromal-derived lactate further stabilizes M2 polarization through a METTL3-TRIB1 program [16]. In parallel, repeated bleeding introduces heme and iron stress that blunts macrophage phagocytosis and efferocytosis [17]. These changes reduce macrophage clearance capacity while favoring repair-like and remodeling programs.

Downstream, vascular endothelial growth factor receptor 1 (VEGFR1⁺) and CD206⁺ macrophage subsets promote vascular endothelial growth factor A (VEGF-A)/transforming growth factor-β (TGF-β)-linked angiogenesis and fibrogenesis, and M2a subsets have been associated with collagen deposition [26–28]. Thus, macrophages contribute to immune escape through a coupled process in which defective phagocytic clearance is paired with vascular, fibrotic, and repair-oriented remodeling. This mechanism links the early failure to remove ectopic tissue with later lesion stabilization within a permissive inflammatory niche.

Impaired cytotoxic surveillance by NK and CD8⁺ T cells

Impaired cytotoxic surveillance represents a second central immune-escape function in endometriosis, involving both innate NK-cell activity and adaptive CD8⁺ T-cell responses (Fig. 1B). Conventional peripheral blood and peritoneal NK cells contribute to early cytotoxic surveillance, whereas uterine NK cells are specialized tissue-resident cells that support vascular remodeling and immune tolerance in the healthy endometrium [29].

In endometriosis, NK-cell dysfunction is driven by coordinated changes in receptor signaling and suppressive peritoneal cues. Inhibitory receptor-ligand signaling increases while activating receptors decrease, shifting NK cells toward reduced killing. A peritoneal milieu enriched in TGF-β, IL-6, and IL-10 further dampens degranulation, interferon-γ (IFN-γ) release, and cytotoxic effector functions [18]. Local lesion-derived signals also weaken target engagement. Endometriotic exosomes impair natural killer group 2 member D (NKG2D)-linked cytotoxicity and promote NK-cell apoptosis [19], while platelet coating of ectopic stromal cells reduces CD107a⁺ degranulation and IFN-γ production, partly through TGF-β/SMAD signaling [20]. Estrogenic signaling may further stabilize this low-reactive state by reducing NKG2D and natural cytotoxicity receptor 1 (NCR1; NKp46) expression, NK cytotoxicity, and IFN-γ production [21]. Soluble intercellular adhesion molecule 1 (ICAM-1) and the expansion of a checkpoint-high CD56⁻CD16⁺ NK-cell subset have also been linked to persistent NK hyporesponsiveness [18]. Together, these changes convert NK cells from an early cytotoxic surveillance arm into a restrained population with reduced degranulation, cytokine release, and target-cell killing.

CD8⁺ T cells form the adaptive cytotoxic arm of anti-lesion surveillance. In endometriosis, CD8⁺ T-cell dysfunction appears to be local and primarily qualitative. Across peritoneal fluid, menstrual effluent, and ectopic lesions, CD8⁺ T cells are maintained or even enriched relative to controls, whereas peripheral blood frequencies remain largely unchanged [30]. Lesion-associated CD8⁺ T cells express lower levels of perforin and granzyme B, produce less tumor necrosis factor-α (TNF-α) and IFN-γ after stimulation, and skew toward memory-like profiles, indicating incomplete cytotoxic competence despite their presence at disease sites [30].

The lesion microenvironment imposes several fitness constraints on CD8⁺ T cells. Endometriotic stromal cells suppress CD8⁺ T-cell proliferation and cytotoxicity, downregulate cytotoxic genes, induce programmed cell death protein 1 (PD-1) through signal transducer and activator of transcription 1 (STAT1) signaling and bias CD8⁺ T cells toward glycolysis [31]. Functional relevance is supported in vivo, as CD8⁺ T-cell deficiency exacerbates lesion growth, whereas transfer of competent CD8⁺ T cells restrains disease [30, 31]. Beyond checkpoint-associated restraint, iron overload can trigger p53-dependent ferroptosis in CD8⁺ T cells, accompanied by lipid peroxidation and glutathione peroxidase 4 (GPX4) loss. Ferroptosis inhibition partially restores CD8⁺ T-cell function while limiting lesions in vivo [32].

Taken together, NK-cell functional restraint and CD8⁺ T-cell dysfunction weaken both innate and adaptive cytotoxic surveillance. This creates a local immune state in which cytotoxic lymphocytes may be present, but their ability to degranulate, release effector cytokines, maintain cytotoxic fitness, and eliminate ectopic targets is insufficient.

Tolerogenic immune priming and regulatory skewing

Within the functional hierarchy summarized in Fig. 1C, tolerogenic immune priming represents another central immune-escape function and begins at the level of antigen presentation. Dendritic cells (DCs) capture and present antigens to T cells and thereby influence whether ectopic endometrial antigens trigger immune activation, non-resolving inflammation, or tolerance. In healthy eutopic endometrium, DCs comprise a balanced mix of immature CD1a⁺ and mature CD83⁺ subsets [33]. In endometriosis, accumulation of immature or tolerogenic DC populations in the peritoneal cavity and lesion sites may weaken effective antigen presentation and shift downstream immune priming toward tolerance [23].

Functional studies support DC maturation as a determinant of lesion control. Experimental induction of DC maturation with intraperitoneal lipopolysaccharide restores a more mature DC profile and reduces lesion burden in early models [34]. Conversely, reprogrammed DC subsets may sustain inflammation without effective clearance. Mannose receptor-expressing myeloid DCs induce IL-1β and IL-6 [35], whereas CD123⁺ plasmacytoid DCs provide lesion-local IL-10 that reinforces immunosuppression and pathological angiogenesis [22]. Pro-angiogenic CD11c⁺MHC-II^lowVEGFR2⁺ DCs [36] and 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1)-driven local cortisol metabolism [24] further support immature, tolerogenic, and lesion-promoting DC states.

DC effects appear stage dependent. Early depletion of CD11c⁺ DCs enlarges lesions and reduces T-cell activation in murine models, underscoring the need for intact antigen presentation during early lesion control [37]. In established disease, however, immature and tolerogenic DC subsets may fail to provide effective co-stimulation and imprint suppressive macrophage, T-cell, and NK-cell responses [23]. These findings position DCs as an upstream regulatory node that influences whether ectopic endometrial antigens initiate immune clearance or local tolerance.

This tolerogenic antigen-presenting environment can shape downstream CD4⁺ T-cell differentiation. In endometriosis, CD4⁺ T-cell lineage imbalance sustains an inflamed yet tolerogenic immune set point. Innate sensing in antigen-presenting cells can bias CD4⁺ T-cell differentiation toward T helper (Th) subsets, including Th1, Th2, and Th17 cells, as well as regulatory T-cell (Treg) states [38], and lesions may contain concurrent Th1 and Th2 responses rather than a single polarized cytokine pattern [39]. A stage-associated shift in the Treg/Th17 balance has also been reported. In peritoneal fluid, Th17 cells increase from minimal or mild to moderate or severe disease, whereas Tregs decrease [40]. A strengthened IL-23/Th17 axis [41] and elevated peritoneal IL-17 [42] further link this inflammatory arm to disease severity and infertility.

Regulatory programs in endometriosis are also functionally heterogeneous. FOXP3⁺CD4⁺ cells include resting and activated suppressive subsets as well as FOXP3^low inflammatory populations, making bulk Treg frequencies difficult to interpret [43]. In advanced disease, IL-24-producing regulatory T and B cells accumulate in peritoneal fluid [44]. In mice, Treg depletion enlarges lesion area and increases peritoneal IL-6 and VEGF [45], suggesting that regulatory programs may restrain inflammatory angiogenesis while still failing to restore effective anti-lesion immunity.

Together, altered DC priming and CD4⁺ lineage skewing support an adaptive immune state in which inflammation persists, regulatory programs are selectively remodeled, and effective lesion elimination remains incomplete. This inflamed yet tolerogenic landscape may further weaken cytotoxic immunity and reinforce checkpoint-associated restraint.

Checkpoint-mediated protection across phagocytic and cytotoxic arms

Checkpoint-mediated protection represents a cross-cutting immune-escape layer that restrains both cytotoxic killing and phagocytic clearance (Fig. 1D). Although immune checkpoints normally prevent excessive immune activation, in endometriosis they may suppress anti-lesion immune responses. Checkpoint-related molecules, including PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and CD47, have been reported across T-cell, myeloid, and stromal compartments in eutopic endometrium, ectopic lesions, and peritoneal fluid [8, 31, 46]. Single-cell and transcriptomic analyses further place checkpoint-related signals across immune and stromal clusters, supporting their involvement in a checkpoint-enriched immune-escape program [47]. Although these inhibitory circuits resemble exhaustion programs described in chronic infection and cancer, they operate within a benign, estrogen-dependent disease context [48, 49].

The peritoneal environment provides sustained inhibitory input. Programmed death-ligand 1 (PD-L1) concentrations are higher in peritoneal fluid than in serum, and PD-L1⁺ DCs increase with disease [50]. In circulation, soluble PD-1 and PD-L1 are elevated compared with controls [51]. On the T-cell side, CTLA-4⁺CD4⁺ and CTLA-4⁺CD8⁺ populations increase together with IL-6 and IL-10, linking checkpoint expression to an inflammatory yet suppressive milieu [46].

Functionally, these checkpoint axes weaken both cytotoxic and phagocytic effector responses. In stromal cell–T-cell co-culture, endometriotic stromal cells increase PD-1 expression on CD8⁺ T cells while reducing IFN-γ⁺ and granzyme B⁺ CD8⁺ subsets and suppressing IFNG, GZMB, and PRF1 expression [31]. A parallel checkpoint-like mechanism affects innate clearance, as CD47^high stromal cells limit macrophage phagocytosis, whereas anti-CD47 treatment enhances macrophage uptake and reduces lesion weight in vivo [8]. Together, these circuits help explain how endometriosis can remain inflamed yet clearance-deficient by restraining cytotoxic lymphocytes, limiting macrophage-mediated phagocytosis, and reinforcing local immune tolerance.

Lesion-supportive inflammatory remodeling and clinical consequences

Lesion-supportive inflammatory remodeling provides a downstream layer of immune escape in which inflammation promotes implantation, tissue remodeling, immune restraint, and clinical symptoms instead of effective lesion clearance (Fig. 1E). Neutrophils and neutrophil extracellular traps (NETs) contribute to this process in a stage-linked manner. Early C-X-C chemokine receptor 2 (CXCR2)-dependent neutrophil influx facilitates lesion establishment, as CXCR2 blockade reduces peritoneal neutrophil recruitment and initial tissue attachment [52], while early anti-Gr-1 treatment lowers lesion number without affecting lesion size in experimental models [53]. After recruitment, neutrophils may stabilize nascent implants by forming NET-like chromatin structures and protease-rich matrices that support fragment retention [52]. The neutrophil secretome can further promote stromal proliferation while reducing CD8⁺ T-cell viability [54]. Clinically, NETosis markers are elevated in peritoneal fluid and circulation and correlate with disease severity, pain, and infertility [55, 56]. In established lesions, neutrophils may also acquire immunosuppressive features, including PD-L1 expression [57, 58]. Thus, neutrophils and NETs connect early attachment, scaffold formation, cytotoxic restraint, and clinically relevant inflammatory remodeling.

Mast cells (MCs) provide another inflammatory remodeling module, linking immune activation to neurovascular remodeling, pain sensitization, and local tissue remodeling. MCs are enriched in endometriotic lesions, particularly in deep infiltrating lesions associated with more severe and refractory symptoms [59]. Estrogen signaling appears to amplify this program, as estradiol replacement expands peritoneal MCs and increases local IL-6 and TNF-α, whereas estrogen receptor blockade reduces MC expansion and cytokine output [60]. Mechanistically, G protein-coupled estrogen receptor 1 (GPR30/GPER1)-dependent estrogen signaling promotes MC-derived fibroblast growth factor 2 (FGF2) secretion and lesion-associated pain-related behaviors [61]. In parallel, activation of the Mas-related G protein-coupled receptor X2 (MRGPRX2)-histamine axis enhances transient receptor potential vanilloid 1 (TRPV1) phosphorylation , whereas MRGPRX2 inhibition reduces lesion volume and dampens pain-related neuronal firing [62]. MC programs may therefore reinforce neuroinflammation, pain, and lesion-supportive remodeling.

Humoral immunity may represent a secondary remodeling layer within the immune-escape landscape of endometriosis. Through autoreactivity, antigen-driven B-cell activation, and regulatory B-cell outputs, B cells and plasma cells may reinforce chronic inflammation and selective immune tolerance. Circulating autoantibodies [63], peritoneal autoantibody reactivity [64], and increased B cells or plasmablasts in eutopic and shed endometrium support systemic and local B-cell involvement in at least a subset of patients [65, 66]. The expanded B-cell compartment may also acquire regulatory features, as IL-10-producing B10 regulatory cells, plasmablasts, and IL-24-producing regulatory T and B cells have been linked to immunosuppressive cytokine production or an immunosuppressive peritoneal microenvironment [44, 67]. In murine models, BTK inhibition with ibrutinib reduces B-cell activity, lesion burden, and fibrosis [10]. Thus, humoral immunity may reinforce chronic inflammation and selective immune tolerance, although its contribution remains less functionally resolved than myeloid-, NK-cell-, and cytotoxic T-cell-centered mechanisms.

Collectively, these inflammatory and humoral remodeling programs indicate that endometriosis does not simply exhibit immune activation or immune suppression in parallel. Instead, lesion-derived cues, clearance failure, cytotoxic restraint, tolerogenic priming, checkpoint-mediated protection, and tissue remodeling converge to generate an inflamed yet clearance-deficient niche. This convergence may help explain why immune escape differs by lesion subtype, disease stage, and clinical phenotype. To link this mechanistic hierarchy with clinically measurable readouts, Table S1 summarizes candidate immune-related biomarkers across peritoneal fluid, blood, menstrual effluent, eutopic endometrium, and ectopic lesions. Although most markers remain insufficiently validated for routine clinical use, this integrated framework may support future patient stratification and biomarker-guided monitoring.

Therapeutic strategies to reinvigorate anti-endometriotic immunity

The mechanistic hierarchy outlined above provides a functional basis for classifying candidate immune-reprogramming strategies according to the escape process they are intended to restore or disrupt. Representative approaches include restoration of macrophage-mediated clearance, recovery of cytotoxic surveillance, modulation of tolerogenic or inflammatory immune programs, and spatially controlled disruption of inhibitory signaling. The following sections focus on selected non-hormonal strategies with mechanistic or preclinical support rather than providing an exhaustive catalogue of immune-directed interventions. Current evidence remains predominantly preclinical, and most approaches should therefore be regarded as experimental and hypothesis-guiding rather than clinically validated treatments for endometriosis. Table 1 summarizes representative small-molecule exemplars, their targeted immune functions, and core readouts, whereas Table S2 provides a broader overview of candidate targets, agents, development stages, and key preclinical endpoints.

Table 1.

Small-molecule exemplars targeting immune-escape programs in endometriosis

Target/axis	Agent(s)	Immune-escape output	Model/level	Representative endpoints	Refs
ERβ–CD47 transcriptional axis	ERβ antagonism (class)	CD47 downregulation; sensitization to CD47–SIRPα disruption	Human tissue + mechanistic assays	CD47 enrichment in CD10⁺ stroma; ERβ-dependent promoter activity	[68]
CD47–SIRPα checkpoint (dual modulation)	RRx-001 (nibrozetone)	CD47–SIRPα downregulation; macrophage phagocytosis restored	Preclinical oncology; endometriosis models to be determined	CD47 ↓ (target cells); SIRPα ↓ (monocytes/macrophages); phagocytosis ↑	[69]
QPCTL/isoQC-dependent CD47 maturation	SEN177; varoglutamstat (PQ912); QP5038	Reduced functional CD47–SIRPα engagement	Cell-based systems + preclinical oncology	CD47–SIRPα interaction ↓; phagocytosis restored	[70–72]
CD47–SIRPα interface antagonism	SMC18	Direct blockade of CD47–SIRPα binding; macrophage phagocytosis restored	Preclinical oncology (screening-derived)	CD47–SIRPα interaction blocked; phagocytosis ↑	[73]
PGI₂–PTGIR axis (NK functional restraint)	RO1138452	Restoration of NK effector function under hypoxia-associated suppression	Mechanistic + in vivo	CD107a/IFN-γ/GZMB ↑; CD16⁻ skewing ↓; lesion-weight increase blunted	[74]
IDO1-Trp catabolism	1-methyl-tryptophan	Treg-linked tolerance attenuation	Experimental models	Treg differentiation/markers ↓; lesion growth ↓	[11]
Polyphenol adjunct (biomarker-outcome gap)	Resveratrol	Biomarker improvement with limited clinical analgesic gain	small RCT	Lesion metrics ↓; IL-6/IL-8/TNF-α/MMP-2/9/VEGF ↓; endometrial VEGF/TNF-α ↓; pain benefit limited	[12, 13, 75]

CD47–SIRPα inhibition

CD47–SIRPα signaling provides a representative clearance checkpoint in endometriosis. As summarized in Fig. 2A, estrogen receptor β (ERβ) has been proposed to reinforce immune evasion by upregulating CD47 in lesion stromal cells [68]. CD47 expression is enriched in the CD10⁺ stromal compartment of ectopic lesions compared with eutopic endometrium (Fig. 2B, C), and mechanistic data suggest that ERβ may act upstream to activate CD47 transcription (Fig. 2D, E). These findings support the concept that CD47^high ectopic stromal cells may resist macrophage-mediated clearance, although the therapeutic relevance of this axis in patients remains to be established.

Fig. 2.

A Schematic overview summarizing ERβ-driven CD47 upregulation. B Representative confocal microscopy images showing expression of CD47, CD10, and nuclei in normal endometrial (NE) and ectopic endometrial (EE) tissue samples. C Representative flow-cytometry histograms showing CD47 expression in gated CD45⁻CD10⁺ stromal cells isolated from NE and EE samples. D Western blot analysis confirming ERβ overexpression in 293T cells. E CD47 promoter luciferase reporter assay showing increased transcriptional activity after ESR2/ERβ overexpression. Selected panels reproduced with permission from Hu et al., Journal of Reproductive Immunology 151, 103,513 (2022). Copyright 2022 Elsevier B.V

Beyond antibody-based approaches, several small-molecule routes have been reported to weaken CD47–SIRPα signaling in a clearance-oriented manner. RRx-001, also known as nibrozetone, has been shown to downregulate CD47 on target cells and SIRPα on monocytes or macrophages, thereby enhancing macrophage phagocytosis in preclinical models [69]. Another druggable entry point is glutaminyl-peptide cyclotransferase-like protein (QPCTL)-dependent CD47 maturation, where tool compounds such as SEN177 [70] and varoglutamstat, also known as PQ912 [71], reduce functional SIRPα engagement in cell-based systems. More potent QPCTL inhibitor chemotypes, including QP5038, have also been reported [72]. Direct small-molecule antagonists are also emerging from screening efforts, as illustrated by SMC18, which was reported to disrupt CD47–SIRPα interaction and restore macrophage phagocytosis in preclinical oncology models [73]. Overall, although CD47–SIRPα is a mechanistically plausible non-hormonal target, its therapeutic application in endometriosis remains experimental, and disease-specific validation of efficacy, safety, and delivery context is still required.

NK-cell activation

In endometriosis, NK cell numbers are broadly preserved, yet their cytotoxic program is attenuated, particularly in the peritoneal milieu. A recent mechanistic study identified a hypoxia-activated prostaglandin I₂ synthase (PTGIS)-dependent prostaglandin I₂ (PGI₂)–prostaglandin I₂ receptor (PTGIR) axis that biases NK cells toward a less cytotoxic CD16⁻ state, as depicted in Fig. 3A [74]. Pharmacological PTGIR antagonism with RO1138452 partially reversed this dysfunctional phenotype in NK-92 cells, increasing degranulation- and cytotoxicity-associated markers, including IFN-γ, CD107a, and granzyme B (Fig. 3B). The pathway dependence was further supported by rescue experiments in which RO1138452 counteracted CD16 suppression under hypoxia-mimicking conditions and following PTGIS upregulation in stromal cells (Fig. 3C, D). In a murine endometriosis model, RO1138452 (800 mg/kg) reduced total lesion weight by approximately 50% in wild-type recipients and by roughly two-thirds in Fcgr3⁻/⁻ recipients (Fig. 3E). These findings identify PTGIR antagonism as a mechanistically plausible route to restore NK cytotoxicity.

Fig. 3.

A Proposed hypoxia-PTGIS/PGI₂–PTGIR axis driving CD16⁻ NK cell differentiation. B RO1138452 reduces CD16⁻ NK-92 frequency and increases CD107a, IFN-γ, and granzyme B. C, D RO1138452 rescues CD16 suppression induced by DMOG and by PTGIS upregulation in human endometrial stromal cells. E RO1138452 attenuates the increase in ectopic lesion weight in vivo. Selected panels reproduced with permission of Springer Nature B.V., from Peng et al., Experimental and Molecular Medicine 54, 890–905 (2022); permission conveyed through Copyright Clearance Center, Inc

Additional ex vivo and in vitro studies further suggest that NK effector defects in endometriosis may be pharmacologically reversible. Brief ex vivo exposure to Helixor A enhances peritoneal NK cytotoxicity across disease stages and increases CD107a-linked degranulation without elevating apoptosis [76]. Interleukin-2 (IL-2) provides a complementary activation route. In patient peripheral blood mononuclear cells, IL-2 increases the proportion of CD107a⁺CD56⁺ NK cells, particularly in the endometriosis group, while TNF-α and IFN-γ remain largely unchanged [77]. In a lesion-facing experimental model, IL-2-activated NK-92 cells killed ectopic stromal targets in an effector-to-target ratio-dependent manner, with target viability reduced by up to approximately 70% at the highest ratio tested. Under these conditions, invasion and migration were also markedly suppressed, with increased apoptosis and downregulation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) signaling [78]. Together, these findings suggest that NK-directed strategies are biologically plausible but remain clinically unvalidated; their translational value will likely depend on lesion-localized or temporally controlled activation rather than systemic immune stimulation.

Regulatory skewing and IL-17-family inflammation

IL-17-family signaling provides one potential route for therapeutically suppressing lesion-supportive inflammatory output, although individual family members should not be considered interchangeable components of the canonical Th17 axis. Yao et al. nominated soluble IL-17C as a tractable node and evaluated MOR106, a neutralizing anti-IL-17 C antibody, in experimental models (Fig. 4A) [79]. Using organoid outgrowth, macroscopic and histologic lesion quantification, and pathway-level protein profiling, they demonstrated that blocking IL-17 C–IL-17RE reversed the IL-17 C-driven expansion phenotype in endometrial organoids (Fig. 4B). In an ovarian endometriosis mouse model, MOR106 was associated with an approximately 40% reduction in lesion volume and lesion area (Fig. 4C, D). Treated lesions also shifted away from an epithelial-mesenchymal transition (EMT)-permissive state and showed reduced activation of the phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt) pathway, as reflected by increased E-cadherin, decreased vimentin and N-cadherin, and reduced PI3K and Akt phosphorylation (Fig. 4E).

Fig. 4.

A Overview schematic summarizing IL-17 C–IL-17RE–PI3K–Akt signaling and its pathological outputs and illustrating pathway blockade as a treatment concept. B Endometrial organoids show increased growth after rhIL-17 C stimulation, which is reduced by anti-IL-17RE or the IL-17 C-neutralizing antibody MOR106. C Representative macroscopic images of ovarian endometriosis lesions after MOR106 treatment. D H&E staining and lesion quantification following MOR106 treatment. E Western blot and quantification of EMT markers and PI3K pathway proteins after MOR106 treatment. Selected panels reproduced with permission from Yao et al., Cell Reports Medicine 6, 102,464 (2025). Copyright 2025 Elsevier Inc

Other strategies to reshape the Treg/Th17 balance include targeting upstream immunometabolic regulators and using lower-intensity adjuncts to blunt convergent inflammatory-angiogenic outputs. IDO1 inhibition with 1-methyl-tryptophan has been proposed as a prototype Treg-directed approach that can restrain experimental lesion growth without global immunosuppression [11]. In parallel, resveratrol offers an orally accessible, low-intensity option. In rat endometriosis models, resveratrol at 1–30 mg/kg reduced lesion volume and histological scores and lowered inflammatory, matrix-remodeling, and angiogenic mediators, including IL-6, IL-8, TNF-α, matrix metalloproteinase-2/9 (MMP-2/9), and VEGF [75]. Together, these examples suggest that cytokine-neutralizing biologics, immunometabolic modulators, and nutraceutical adjuncts may suppress regulatory, inflammatory, angiogenic, and matrix-remodeling programs in experimental settings.

Overall, immunomodulatory strategies in endometriosis remain at an early and predominantly preclinical stage. Existing studies provide proof-of-concept that immune circuits can be perturbed to reduce lesion burden or reshape local immune states, but robust clinical evidence remains limited. Translation is further constrained by safety, reproductive relevance, and the need for disease-context-specific targeting. Unlike malignant disease, endometriosis involves a reproductive organ system in which immune homeostasis is tightly linked to fertility, implantation, and tissue repair. This context gives systemic immune activation or prolonged checkpoint modulation a narrow therapeutic window and supports lesion-confined or time-limited immune modulation, for which nanotechnology may offer a practical enabling platform.

Nanotechnology-enabled therapeutic reprogramming in endometriosis

Because systemic immune modulation may disrupt fertility-relevant tissue homeostasis and systemic immune balance, nanotechnology offers a means to improve the spatial and temporal control of immune-directed therapy in endometriosis. Through lesion-enriched accumulation, peritoneal retention, modular payload design, and stimuli-responsive release, nanoscale platforms may increase local exposure while reducing off-target immune activation. This delivery-based advantage is particularly relevant in a benign, chronic, and fertility-sensitive disease. Representative nanotechnology-assisted strategies are summarized in Table 2.

Table 2.

Nanotechnology-assisted immune reprogramming strategies in endometriosis

Platform (material)	Targeting mode	Cargo/mechanism	Immune axis addressed	Model & key readouts	Outcome summary	Classification	Refs.
PLGA-anti-CTLA-4 NPs	Local retention (sustained release)	Checkpoint blockade (protein)	Treg ↓, CD4⁺CD25⁺ modulation; IL-10/TGF-β ↓	Mouse EM; cytokines, Treg frequency, lesion indices	Greater suppression vs. free antibody; ~2-week controlled release	CTLA-4 blockade	[80]
Aptamer-NP (PD-L1 siRNA)	Active (aptamer)	PD-L1 gene silencing	Restores CD8⁺ effector function	Cancer models; PD-L1 knockdown, EMT markers (transferable blueprint)	Robust PD-L1 knockdown; chassis applicable to EM	PD-L1 RNAi	[81]
BSA (albumin) NPs-SPARC targeting	Active (SPARC in M2/lesion)	Mifepristone; (immunogenic cell death) ICD-like effects	Macrophage repolarization (M2→M1), niche drug accrual	Mouse EM; drug biodistribution, M1/M2 markers, lesion burden	Higher intralesional drug, M1 shift, superior inhibition vs. free drug	Macrophage targeting	[82]
CaCO₃ NP (BML-111)	Microenvironment-responsive Ca²⁺ release	Pro-resolving agonist; efferocytosis ↑	Clears apoptotic burden; macrophage function restoration	Mouse EM; apoptosis in ESCs, efferocytosis, safety	Lesion reduction with no detectable side effects	Pro-resolving therapy	[83]
OMV-coated PLGA NPs	Patterned PAMP presentation	Trained-immunity-like reprogramming	M1 ↑/M2 ↓; TGF-β, α-SMA ↓; supports NK/T	Mouse EM; immunohistochemistry (CD163, CD206, TGF-β, α-SMA), cytokines	Lesion-site immuno-remodeling; prevention efficacy	Macrophage reprogramming	[84]
Fe3O4-based magnetic labeling nanoparticles	External magnetic guidance (field-assisted homing)	Magnetic labeling of adoptive NK cells to aid trafficking/retention	NK trafficking and target-site enrichment	Tumor models; NK infiltration; effective loading; Ki-67/apoptosis	Field-guided accumulation increases intratumoral NK density and improves antitumor readouts	Magnetic homing	[85, 86]

Lesion-facing and microenvironment-responsive nanoplatforms for macrophage reprogramming

Macrophage reprogramming is a relevant experimental target in endometriosis, and several nanoplatforms have been developed to improve local drug exposure or macrophage-associated delivery in preclinical models. One illustrative example is a secreted protein acidic and rich in cysteine (SPARC)-mediated bovine serum albumin nanoparticle system loaded with mifepristone (BSA@Mif NPs), which was developed to enrich mifepristone within lesions (Fig. 5A) [82]. In vitro, BSA@Mif NPs showed enhanced cellular uptake in M2-type macrophages compared with free mifepristone (Fig. 5B, C, D). In vivo, whole-body imaging showed preferential accumulation of BSA@Mif NPs in endometriotic lesions (Fig. 5E), and drug quantification confirmed higher mifepristone levels in ectopic lesions than after free mifepristone administration, with peak accumulation at 24 h post-injection (Fig. 5F). This was associated with reduced ectopic lesion weight compared with free mifepristone (Fig. 5G), and a shift in the lesion macrophage profile, reflected by an increased M1-like/M2-like macrophage ratio (Fig. 5H). These findings support the feasibility of coupling lesion-enriched delivery with macrophage phenotypic modulation in animal models, although whether such effects translate into durable clinical benefit or improved reproductive safety remains unknown.

Fig. 5.

A Scheme of BSA@Mif NPs regulating the immune microenvironment of endometriosis. B Fluorescence images of M2-type BMDMs treated with free C6 or BSA@C6 NPs. C Flow cytometry analysis of M2-type BMDMs treated with free C6 or BSA@C6 NPs. D Statistical analysis of (C). E Whole-body imaging at the indicated time points. F Mifepristone levels in the uterus and ectopic lesions 4 and 24 h after i.v. injection of free mifepristone plus DiR or DiR-labeled BSA@Mif NPs. In vivo anti-endometriosis effects of BSA@Mif NPs, shown as ectopic lesion weight (G) and M1/M2 macrophage ratio in lesions H. Selected panels reproduced with permission from Zhang et al., Acta Biomaterialia 189, 505–518 (2024). Copyright 2024 Elsevier Ltd

Beyond ligand-guided homing, other designs exploit the peritoneal compartment or lesion-associated microenvironment to increase macrophage engagement and restrict payload activation. Wu et al. used an outer membrane vesicle (OMV)-coated poly(lactic-co-glycolic acid) (PLGA) nanoplatform to preferentially engage peritoneal macrophages; at 24 h, macrophages represented 81.5% of DiD-positive peritoneal cells, suggesting macrophage-associated delivery within the peritoneal cavity [84]. In parallel, Sun et al. developed an acid-sensitive CaCO₃ nanoparticle system for microenvironment-gated delivery of the pro-resolving mediator BML-111 and treated surgically induced endometriosis mice by intravenous dosing every two days for ten injections [83]. BML@CaNP reduced ectopic lesion burden by about 70% across weight and size measures, while concurrently restoring macrophage clearance capacity as indicated by a marked increase in phagocytic index and lowering inflammatory load in peritoneal fluid as reflected by reduced IL-1β, with stable body weight over the treatment course [83].

Together, these studies support the feasibility of spatially controlled macrophage-directed delivery in preclinical endometriosis models, but its therapeutic relevance requires further validation.

Nanotechnology-enabled restoration of NK cytotoxicity

Rather than serving as an endometriosis-specific efficacy model, NK-directed nanotechnology is discussed here as a transferable engineering concept for coupling immune activation to controlled in vivo behavior. The CSF@E-Hn nanosystem provides an example of coupling tissue tropism with endogenous NK cell activation. By using hematopoietic stem cell-derived nanovesicles decorated with anti-PD-L1 antibody (aPD-L1) and anti-NKG2D antibody (aNKG2D) and loaded with colony-stimulating factor (CSF), this platform was designed to bring target cells and NK cells together within the bone marrow niche [87].

Physical steering approaches provide another transferable principle. Magnetic nanoparticle loading (e.g., Fe₃O₄/SiO₂ core-shell nanoparticles) markedly improved NK infiltration (reported up to 17-fold) without compromising killing activity [85], and Fe₃O₄@polydopamine labeling enhanced NK accumulation under a magnetic field with stronger functional outputs in vivo [86]. Cationic nanoparticles further show that nanomaterials may directly tune NK cell functional states, with reported enhancement of NK cell cytotoxicity and altered CCR4 and CXCR4 expression after nanoparticle treatment [88]. Although derived from non-endometriosis models, these examples suggest that NK-directed nanotechnology may do more than improve payload delivery; it may couple immune activation with spatially controlled biodistribution by coordinating NK–target cell encounter, local NK cell enrichment, and cytotoxic readiness or homing behavior.

Peritoneum-retentive and ligand-directed nanoparticles for local checkpoint blockade

Lesion-level heterogeneity in checkpoint expression makes systemic blockade difficult to justify for a benign, chronic, and fertility-relevant disease [8]. Nanoplatforms that restrict checkpoint modulation to the peritoneal or lesion-proximal immune niche have therefore been proposed as a cautious design direction, although this concept remains largely untested in endometriosis. Aptamer-functionalized PD-L1 small interfering RNA (siRNA) nanoparticles provide a transferable nucleic acid blueprint [81]. In this system, PD-L1 siRNA is encapsulated in PLGA-PEG cores by double emulsion, and a nuclease-resistant RNA aptamer on the surface drives uptake into PD-L1^high tumor cells [81]. In vitro, these particles entered target cells, reduced PD-L1 within 48 h, and limited migration with minimal off-target toxicity; in xenografts, they slowed tumor growth and restored CD8⁺ infiltration [81, 89]. This example illustrates ligand-directed checkpoint modulation with greater spatial selectivity than systemic blockade.

Zhou et al. demonstrated that NP-TP1@M-M nanoparticles, when combined with chemotherapy and immune checkpoint blockade, enable spatially confined immune modulation within the peritoneal compartment in an ovarian cancer model. Facilitated by antigen capture (Fig. 6A), the nano-vaccine serves as a delivery platform for in situ antigen handling and presentation [90]. Fluorescence imaging (Fig. 6B) revealed time-dependent accumulation in draining lymph nodes, confirming efficient targeting of immune-enriched tissues. The 2.5-fold increase in lymph-node fluorescence intensity (Fig. 6C, D) suggested enhanced antigen routing to immune-priming sites. Consistent with this localized immune engagement, Fig. 6E shows that, when combined with chemotherapy and aPD-L1, NP-TP1@M-M prolongs disease control in ID8-luc tumor-bearing mice. Although this example is not an endometriosis treatment model, it illustrates how nanoparticle-mediated delivery may confine checkpoint-related immune activation to a defined anatomical niche. For endometriosis, such approaches remain conceptual and will require disease-specific validation of local immune modulation, reproductive safety, and clinically meaningful efficacy.

Fig. 6.

A Schematic illustration of antitumor immunity induced by nano-vaccine NP-TP1@M-M in combination with chemotherapy and immune checkpoint blockade. B Fluorescence images of mice 1, 2, and 4 h after local injection of DiR-labeled NPs and AC-NPs, with draining lymph nodes marked by red circles. C Fluorescence images of isolated lymph nodes and major organs 4 h after the administration of nano-vaccines. D Quantitative fluorescence signals at the draining lymph nodes based on in vivo imaging data shown in (B). E Fluorescence images of ID8-luc tumor-bearing mice treated with various regimens, showing tumor progression over time after luciferase substrate injection and quantified abdominal fluorescence signals. Selected panels reproduced with permission from Zhou et al., Journal of Nanobiotechnology 22, 483 (2024), Springer Nature; reproduced with permission from SNCSC

Lessons from cancer immunotherapy for endometriosis

Biomarker discovery and patient stratification via multi-omics

Multi-omics strategies from oncology may still be useful in endometriosis, but their value here lies less in generating larger molecular catalogs than in resolving clinically meaningful heterogeneity. Endometriosis is unlikely to be immunologically uniform across lesion types, stages, or sampling compartments. Recent immune-focused reviews indicate that ovarian endometriosis tends to combine lesion-level immunosuppression with measurable systemic inflammatory change, whereas deep infiltrating disease is more often linked to complement-associated tissue injury and activation of IDO1-, COX-2-, and MMP-9-related programs [91]. A comparative peripheral blood study further found that ovarian endometriosis was associated with increased monocyte counts and reduced neutrophil proportions, whereas deep infiltrating disease showed higher IL-8 and galectin-1 levels [92]. These observations argue against treating immune biomarkers as subtype-agnostic signals.

Stage also seems to matter, although current evidence remains uneven. Cross-sectional evidence suggests that earlier and advanced disease may differ in the relative balance of inflammatory, suppressive, and fibrotic programs. However, current data do not establish a uniform longitudinal transition from one immune state to another. At the same time, symptom burden does not map neatly onto stage, and pain severity cannot be inferred directly from disease stage or immune profile alone [91].

Clinical interpretation should therefore be endpoint-specific. Pain likely reflects not only inflammation, but also lesion location, fibrosis, innervation, and neuroimmune remodeling [92, 93]. By contrast, endometriosis-associated infertility is more plausibly linked to a combined lesion-proximal and eutopic endometrial immune-inflammatory state that may impair gamete interaction, implantation, and pregnancy maintenance [94]. Recurrence adds further complexity because lesion recurrence and symptom relapse are not synonymous, and both are shaped by disease subtype, surgical completeness, follow-up duration, and postoperative treatment.

Advanced immunoengineering strategies borrowed from oncology

Advanced immunoengineering strategies developed in oncology may provide conceptual guidance for studying immune escape in endometriosis, but their therapeutic relevance remains speculative. Programmable cell-based platforms, such as logic-gated synthetic receptor systems, demonstrate how immune activation can be spatially and contextually constrained. In cancer models, synthetic Notch (synNotch)- and chimeric antigen receptor (CAR)-based circuits implement conditional activation, local effector release, or checkpoint modulation only within defined antigenic niches, thereby enhancing specificity and reducing off-target immune toxicity [95, 96]. Similar logic-gated architectures could, in principle, be adapted to restrict immune activation to the peritoneal microenvironment of endometriotic implants.

Recent studies indicate altered PD-1/PD-L1-related signaling in endometriosis across immune subsets and biological compartments, suggesting potential value for exploratory biomarker stratification [49–51]. These findings suggest that checkpoint pathways may provide stratification clues, but they do not establish systemic checkpoint blockade as an appropriate therapeutic strategy. Other oncology-derived tools, such as checkpoint-targeted protein degraders [97, 98], remain distant from endometriosis application and would require particular caution because sustained PD-1/PD-L1 suppression could theoretically interfere with reproductive immune tolerance and tissue repair.

Among oncology-derived technologies, genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) perturbation screens may have the most immediate translational value as discovery platforms. Applied to lesion-derived organoids, stromal cells, or peritoneal immune co-cultures, such platforms could help identify context-specific tolerance nodes and distinguish disease-relevant immune escape mechanisms from broader inflammatory dysregulation [99, 100]. This would allow immune escape mechanisms in endometriosis to be prioritized on disease-specific functional evidence, rather than inferred from cancer models.

Prospects of endometriosis vaccines

Therapeutic cancer vaccines demonstrate that vaccination can reinforce post-surgical immune surveillance. In high-risk resected melanoma, KEYNOTE-942 showed improved recurrence-free survival when personalized mRNA vaccine mRNA-4157 (V940) was added to pembrolizumab, alongside stronger neoantigen-specific T cell responses [101]. Similar signals in melanoma [102] and pancreatic cancer [103] provide a conceptual rationale for considering whether vaccine-like strategies could be explored in recurrent endometriosis.

However, endometriosis differs fundamentally from cancer because it lacks abundant mutational neoantigens and occurs in a reproductive immune environment where tolerance is physiologically important. Therefore, any vaccine concept would need to redefine “targetable antigen” away from classic tumor neoantigens. Candidate targets may include lesion-enriched self-proteins, post-translationally modified epitopes, or pathogen-associated determinants in infection-linked subsets, which would need to be identified by proteogenomic and human leukocyte antigen (HLA) peptidomic profiling rather than mutation calling alone [49, 104]. Design principles from oncology may still be informative, including epitope selection based on HLA binding, lesion coverage, limited expression in fertility-critical tissues, and the capacity to induce balanced helper and cytotoxic T cell responses [101, 102].

Clinically, endometriosis vaccines would most plausibly be developed as perioperative or maintenance interventions, aiming to prevent reimplantation, clear microscopic deposits, and reprogram the peritoneal niche away from tolerance. Platforms could range from peptide or mRNA formulations with immune-stimulating adjuvants to dendritic cell-based vaccines pulsed with lesion antigens, potentially combined with checkpoint blockade or nanocarrier-enabled local delivery to limit systemic autoimmunity [103, 104]. Overall, endometriosis vaccines remain highly speculative and would require identification of disease-relevant antigens, validation in models that capture both chronic inflammation and reproductive tolerance, and evaluation of outcomes such as recurrence, pain, and fertility. More broadly, cancer immunotherapy offers useful conceptual and technical references for endometriosis, but it should not be treated as a direct therapeutic template. Future translation should prioritize local and reversible immune modulation, reproductive safety, and clinically meaningful benefit beyond immune activation itself.

Conclusion

Endometriosis can be understood not only as a disorder of immune dysregulation, but also as a lesion-centered immune-escape framework in which defective clearance, impaired cytotoxic surveillance, tolerogenic priming, checkpoint-mediated protection, and lesion-supportive inflammatory remodeling converge to permit ectopic tissue persistence despite ongoing immune activation. This mechanistic hierarchy integrates evidence from peritoneal fluid, eutopic endometrium, and ectopic lesions, and provides a functional basis for understanding angiogenesis, fibrosis, pain, recurrence, infertility, and disease heterogeneity.

Future translation should prioritize disease-specific, locally controlled, and reversible immune modulation rather than broad systemic activation. Key priorities include validating immune targets across lesion subtypes and disease stages, developing accessible biomarker panels linked to clinically meaningful outcomes, and confirming local pharmacodynamic target engagement. Given the benign and fertility-relevant nature of endometriosis, immune-directed strategies must also demonstrate reproductive safety, appropriate patient selection, scalable delivery, and benefit in outcomes such as pain, recurrence, fibrosis, and fertility preservation. Nanotechnology, biomarker-guided intervention, and cautiously adapted principles from cancer immunotherapy may support this transition toward more precise and hormone-sparing treatment strategies, but substantial disease-specific validation remains necessary.

Abbreviations

Akt

Protein kinase B

BSA

Bovine serum albumin

BSA@Mif

Bovine serum albumin nanoparticles loaded with mifepristone

BTK

Bruton’s tyrosine kinase

DCs

Dendritic cells

CTLA-4

Cytotoxic T-lymphocyte-associated protein 4

ERβ

Estrogen receptor β

Fe₃O₄

Magnetite (iron(II, III) oxide)

FOXP3

Forkhead box protein P3

IDO1

Indoleamine 2,3-dioxygenase 1

IFN-γ

Interferon-γ

IL

Interleukin

mRNA

Messenger RNA

M1

Classically activated macrophage phenotype (M1-like)

M2

Alternatively activated macrophage phenotype (M2-like)

MCs

Mast cells

NETs

Neutrophil extracellular traps

NK

Natural killer

NKG2D

Natural killer group 2 member D

NPs

Nanoparticles

PD-1

Programmed cell death protein 1

PD-L1

Programmed death-ligand 1

PI3K

Phosphoinositide 3-kinase

PLGA

Poly(lactic-co-glycolic acid)

PTGIR

Prostaglandin I₂ receptor

siRNA

Small interfering RNA

S1P

Sphingosine-1-phosphate

SIRPα

Signal regulatory protein α

SMAD

Suppressor of mothers against decapentaplegic

SPARC

Secreted protein acidic and rich in cysteine

TGF-β

Transforming growth factor-β

Th

T helper

TNF-α

Tumor necrosis factor-α

Treg

Regulatory T cell

VEGF

Vascular endothelial growth factor

Authors’ contributions

Huiting Chen: Writing - original draft, Writing - review & editing. Meng Zhang: Writing - original draft, Visualization. Weidong Fei: Funding acquisition, Writing - review & editing, Visualization. Qiqin Zhang: Data curation, Writing - review & editing. Yujie Peng: Formal analysis, Writing - review & editing. Libo Zhu: Data curation, Writing - review & editing. Shaojie Ding: Resources, Writing - review & editing. Xian Zhang: Funding acquisition, Writing - review & editing. Zhengyun Chen: Conceptualization, Funding acquisition, Supervision, Writing - review & editing. Mengdan Zhao: Conceptualization, Funding acquisition, Project administration, Writing - original draft, Writing - review & editing.

Funding

This work was financially supported by the National Natural Science Foundation of China (82401930, 82071616, and 82001518), Zhejiang Provincial Natural Science Foundation of China (Grant No. LQN25H270002), and the 4 + X Clinical Research Project of Women’s Hospital, School of Medicine, Zhejiang University (ZDFY2021-4 × 202).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.