Immune-epigenetic-metabolic crosstalk: attempting to unravel the multidimensional mechanisms of immune evasion in endometriosis

Wenyu Xu, Juan Du
In: Frontiers in Immunology · 2026 · vol. 17 · doi:10.3389/fimmu.2026.1855106 · W7168300481
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Abstract

The survival of ectopic endometrial lesions in endometriosis critically depends on their ability to evade immune recognition and clearance by the host, a process known as immune evasion. Recent studies suggest that this process is not driven by a single factor but rather results from a multidimensional, interactive regulatory network involving immune dysregulation, epigenetic remodeling, and metabolic reprogramming. The pathophysiology of endometriosis is characterized by reduced cytotoxic activity and functional exhaustion of effector immune cells, along with excessive activation and expansion of immunosuppressive cells, affecting both innate and adaptive immunity. The overexpression of immune checkpoint molecules further impairs immunological clearance. DNA methylation, histone modifications, and non-coding RNAs contribute to immune cell tolerance by stabilizing repressive transcription programs and silencing pro-inflammatory genes. These epigenetic mechanisms maintain a sustained immunosuppressive state through direct regulation of immune-related genes and hormone-metabolizing enzymes. Additionally, the hypoxic environment of ectopic lesions stimulates glycolysis, leading to the accumulation of metabolites such as lactate. Beyond directly impairing immune cell function, these metabolites act as signaling molecules or cofactors for epigenetic enzymes, thereby influencing chromatin states and gene expression, thus mechanistically and functionally linking metabolism to epigenetics. This review aims to systematically unravel this multidimensional mechanism, elucidate its synergistic role in disease progression, and potentially pave the way for future combined therapeutic strategies targeting this complex pathway. Such approaches offer a novel and promising means to overcome immune evasion and clinical resistance in endometriosis.

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