Dysfunction of natural killer cells promotes immune escape and disease progression in endometriosis

Weiyu Jiang, Wen Xu, Feng Chen
Frontiers in immunology · 2025 · vol. 16 , pp. 1657605 · doi:10.3389/fimmu.2025.1657605 · PMID:40977720 · PMC12446245 · W4414027656
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⚙ AI-generated summary by claude@2026-06, 2026-06-07 ⓘ

Natural killer cell dysfunction, driven by aberrant receptor-ligand interactions and elevated immunosuppressive cytokines, promotes immune escape and disease progression in endometriosis by impairing the elimination of ectopic endometrial lesions.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-07 ⓘ

This paper reviews evidence that natural killer (NK) cells are dysfunctional in endometriosis, focusing on how receptor–ligand imbalance, immunosuppressive cytokines (TGF-β, IL-6, IL-10), and adhesion-molecule defects impair NK cytotoxicity and thereby promote survival and implantation of ectopic endometrial lesions. It synthesizes findings from studies assessing NK proportions and function in peripheral blood and peritoneal fluid, and discusses mechanistic links such as reduced NKG2D, altered expression of MICA/MICB, increased inhibitory signaling via NKG2A–HLA-E and HLA-G, and blockade of immunological synapse formation through soluble ICAM-1. A key caveat highlighted is that many cytotoxicity assays use K562 targets that are not MHC-class-I representative of endometriosis-specific interactions, and that direct testing against autologous ectopic endometrial cells is technically limited, leaving uncertainty about eutopic endometrial cytotoxicity. The paper relates to endometriosis by centrally analyzing NK cell immune escape mechanisms, including inhibitory receptor pathways and adhesion/cytokine-mediated suppression, that drive lesion persistence and disease progression in endometriosis.

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Abstract

Endometriosis (EMs) is a chronic inflammatory disorder characterized by dysregulated innate immunity, particularly impaired cytotoxic function of natural killer (NK) cells. As pivotal effectors of the innate immune response, NK cells fail to eliminate ectopic endometrial lesions due to aberrant receptor-ligand interactions, elevated levels of immunosuppressive cytokines (TGF-β, IL-6, and IL-10), and dysfunction of adhesion molecules. This compromised immune surveillance facilitates the survival and implantation of ectopic lesions, contributing to the hallmark symptoms of pain and infertility. Recent immunotherapeutic strategies, including NK cell checkpoint blockade (anti-NKG2A, anti-PD-1), IL-2-based activation, and adoptive NK cell transfer-seek to restore NK cell cytotoxicity and reestablish immune homeostasis. This review summarizes current advances in understanding NK cell dysfunction in EMs, emphasizing its central role in immune evasion and the therapeutic promise of targeting innate immune pathways.

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Condition tags

endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis

Citation neighborhood

Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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