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

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.