Why NK Cells Fail in Endometriosis?

Autophagy, metabolism, exosomes, and cell–cell interactions converge to impair NK cell function in endometriosis

Key Points

Highlights:

• Natural killer (NK) cell dysfunction is a central immune abnormality in endometriosis.
• Multiple mechanisms converge to impair NK cell cytotoxicity, enabling lesion survival and immune escape.

Importance:

• NK cells are critical for eliminating ectopic endometrial cells; understanding why they fail provides insight into disease persistence and recurrence.
• Identifying the mechanisms underlying NK cell dysfunction may open new avenues for immunomodulatory therapies in endometriosis.

What's Done Here?

• This narrative review synthesizes current evidence on NK cell biology in endometriosis.
• The authors integrate data from human studies and experimental models to describe how immune, metabolic, and cellular pathways disrupt NK cell function.
• Emerging mechanisms—including autophagy, metabolic reprogramming, extracellular vesicles, and intercellular interactions—are critically evaluated.

Key Results:

• NK cell cytotoxic activity is consistently reduced in endometriosis, despite preserved or increased cell numbers.
• Altered cytokine signaling, inhibitory receptor engagement, and impaired immune synapse formation weaken NK cell–mediated clearance.
• Lesion-derived factors induce metabolic dysfunction and autophagy changes in NK cells, further reducing their killing capacity.
• Exosomes and cell–cell material transfer (trogocytosis) emerge as novel contributors to immune evasion.
• Collectively, these mechanisms create an immune-tolerant microenvironment that supports lesion establishment and persistence.

 Strengths and Limitations:

• Strengths are: comprehensive integration of classical and emerging immune mechanisms, and a clear conceptual framework linking NK cell dysfunction to immune escape.
• Limitations are: reliance on heterogeneous studies with variable methodologies and limited direct translational or interventional data.

From the Editor-in-Chief – EndoNews

"Endometriosis has long been described as a hormonally driven inflammatory disease, yet this framing alone fails to explain one of its most defining features: the ability of ectopic lesions to persist despite immune surveillance. This comprehensive review places natural killer (NK) cell dysfunction at the center of that paradox and, in doing so, reframes endometriosis as a condition of active immune escape rather than passive immune tolerance.

What distinguishes this work is its movement beyond receptor-level explanations toward a more integrated immunobiological model. The authors convincingly show that reduced NK cell cytotoxicity in endometriosis cannot be attributed to a single defect. Instead, it emerges from the convergence of altered cytokine environments, inhibitory signaling, disrupted immune synapse formation, and—critically—newer mechanisms such as metabolic reprogramming, dysregulated autophagy, extracellular vesicle transfer, and trogocytosis. Together, these processes progressively blunt NK cell function while preserving NK cell presence, creating the illusion of immune competence where functional failure exists.

Particularly important is the emphasis on lesion-driven immune reprogramming. Endometriotic tissue is not portrayed as a passive target of immune dysfunction, but as an active participant that reshapes NK cell behavior through metabolic stress, vesicle-mediated communication, and altered cell–cell interactions. This perspective aligns endometriosis with broader concepts of immune escape seen in oncology and chronic inflammatory disease, while remaining firmly grounded in reproductive immunology.

The review also carries translational significance. If NK cell dysfunction is sustained by metabolic and autophagic alterations, then restoring cytotoxicity may require strategies that go beyond immune activation alone. This insight challenges simplistic immunostimulatory approaches and instead supports a future direction focused on immune recalibration, targeting cellular metabolism, vesicle signaling, and microenvironmental crosstalk. Such approaches could complement hormonal and surgical treatments, particularly in patients with recurrent or refractory disease.

Importantly, the authors maintain appropriate scientific caution. The field remains limited by heterogeneous study designs and a lack of interventional trials directly targeting NK cell pathways in endometriosis. Nonetheless, by integrating classical immunology with emerging cellular biology, this review provides a coherent framework that clarifies where the field stands—and where it must go next.

In sum, this article advances endometriosis research by shifting the conversation from whether immune dysfunction exists to how immune escape is actively constructed and maintained. It invites the field to consider endometriosis not only as a disease of hormones and inflammation, but as one of dynamic immune negotiation, with NK cells at the center of that dialogue." 

Lay Summary

Endometriosis persists in the body despite the presence of immune cells that are normally responsible for eliminating abnormal tissue. One such immune cell type is the natural killer (NK) cell, which plays a key role in identifying and destroying cells that appear in the wrong place.

This review article, written by a team led by Dr.Esmaeil and published in the American Journal of Reproductive Immunology, examines why NK cells fail to perform this protective role in people with endometriosis.

Rather than being absent, NK cells in endometriosis are often present in normal or even increased numbers.

The problem lies in their function. Research summarized in this review shows that NK cells lose their ability to effectively recognize and kill ectopic endometrial cells. This impairment results from several interacting mechanisms, including altered immune signaling, inhibitory receptor activation, and disrupted communication between immune cells and endometriotic lesions.

The authors highlight newer concepts that go beyond traditional immune pathways. Changes in cellular metabolism and autophagy reduce the energy and machinery NK cells need to function properly. In addition, extracellular vesicles (exosomes) released by lesions and abnormal cell–cell interactions, such as trogocytosis, further weaken NK cell responses. Together, these processes create an immune environment that allows endometriotic tissue to survive and grow.

By bringing together both established and emerging evidence, this review underscores that endometriosis is not only a hormonal or inflammatory condition but also a disease of immune escape. Understanding how NK cell dysfunction develops may help guide future research toward immune-based treatment strategies aimed at restoring the body’s natural ability to control the disease.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40758173/