Natural killer cell dysregulation in polycystic ovary syndrome: immunometabolic and reproductive implication

Ningxiao Jiang; Jun Liu; Chanyu Li; Xiuju Wang; Yiwei Pang; Xianghui Zhang; Yixuan Ma; Shinan Zhang; Yingjiang Xu; Qingchun Li; Qinglei Sun; Peiyi Tang; Lei Han

doi:10.3389/fimmu.2026.1781451

PMOS / PCOS Pathophysiology

Natural killer cell dysregulation in polycystic ovary syndrome: immunometabolic and reproductive implication

Jiang N, Liu J, Li C, Wang X, Pang Y, Zhang X, Ma Y, Zhang S, Xu Y, Li Q, Sun Q, Tang P, Han L

Frontiers in immunology, 17, 1781451, 2026

DOI 10.3389/fimmu.2026.1781451 PMID 42064078 PMC PMC13124581

RRM Academy Synopsis

Natural killer cells appear altered in PCOS, with mixed evidence

A 2026 review of animal and human studies reports that natural killer cells look altered in polycystic ovary syndrome (PCOS). Results differ across studies. PCOS now has a new name: polyendocrine metabolic ovarian syndrome (PMOS).

Study at a glance, narrative review: Natural killer cells appear altered in PCOS, with mixed results. Source: Jiang N et al., 2026, PMID 42064078.

Key Findings

Some studies report more natural killer (NK) cells in the blood of infertile women with PCOS than in healthy controls. Other research does not support this.
In the uterine lining after ovulation, uterine NK cells were fewer in infertile women with PCOS, alongside lower local signals from IL-15, IL-18, and CXCL10.
Studies indicate certain killer immunoglobulin-like receptor (KIR) gene variants occur more often in women with PCOS. The authors say direct tests of NK cell function are still needed.
In DHEA-induced mouse models of PCOS, activated NK cells rose in the ovary and uterine NK cells expanded. An androgen receptor blocker reversed these changes.
In obese mice, IL-6/Stat3 signaling produced a myeloid-feature NK (myNK) cell subset tied to worse insulin resistance. The authors call proof of this link in women with PCOS insufficient.

Interpretation

This narrative review brings together animal and human studies on natural killer cells in PCOS. The review points to immune activity as a possible driver of PCOS, alongside the already established roles of high androgens and insulin resistance. The authors note that direct tests of NK cell function in women with PCOS are still needed. The findings support larger, controlled studies of NK cell activity in women with PCOS.

RRM Context

Restorative reproductive medicine looks for the root cause of a disrupted cycle. This review adds immune activity to a list that already includes high androgens and insulin resistance. Root-cause care already addresses those two drivers.

Our editorial summary of this paper, not the article's abstract.

Abstract

Polycystic ovary syndrome (PCOS), a complex endocrine and metabolic disorder, involves significant dysregulation of the immune system. Natural killer (NK) cells, as key components of innate immunity, demonstrate notable phenotypic and functional alterations in women with PCOS. These changes include not only an elevated proportion in peripheral blood but also dynamic shifts within the local microenvironments of the ovary and endometrium. The increased level of peripheral NK cells correlates with a chronic low-grade inflammatory state, potentially serving as a predictive marker in infertile PCOS patients. Within the endometrium, uterine NK (uNK) cells exhibit reduced numbers and impaired function, accompanied by dysregulation of cytokine networks such as IL-15 and IL-18, which disrupts the immune equilibrium essential for embryo implantation. Abnormal NK cell function further involves alterations in killer immunoglobulin-like receptor (KIR) repertoires and dysregulated secretion of angiogenic factors, thereby compromising endometrial receptivity and vascular remodeling. Hyperandrogenemia modulates the distribution and activity of NK cells in reproductive tissues by influencing their surface activation markers, while insulin resistance promotes the generation of myeloid-feature NK (myNK) cell subsets via the IL-6/Stat3 signaling pathway, collectively exacerbating metabolic inflammation and reproductive dysfunction. Deciphering the role of NK cells in the immunometabolic interplay of PCOS reveals their position as a critical link between. May represent a potential cutoff requiring validation in larger cohorts reproductive impairment and metabolic disturbances, opening new avenues for targeted immunomodulatory interventions. Collectively, NK cells appear to present an important immunometabolic link between reproductive dysfunction and metabolic disturbance in PCOS, highlight their potential relevance as therapeutic targets.

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Topics

PMOS / PCOS › Pathophysiology › Insulin Resistance · Genetics and Immunology › Reproductive Immunology › Implantation Immunology

Ningxiao Jiang, Jun Liu, Chanyu Li, Xiuju Wang, Yiwei Pang, Xianghui Zhang, Yixuan Ma, Shinan Zhang, Yingjiang Xu, Qingchun Li, Qinglei Sun, Peiyi Tang, Lei Han

N Jiang, J Liu, C Li, X Wang, Y Pang, X Zhang, Y Ma, S Zhang, Y Xu, Q Li, Q Sun, P Tang, L Han

PMID 42064078 42064078 DOI 10.3389/fimmu.2026.1781451 10.3389/fimmu.2026.1781451 Jiang et al. 2026, Jiang 2026

Keywords

chronic inflammation, hyperandrogenism, immunometabolism, insulin resistance, natural killer cell, polycystic ovary syndrome, uterine NK cells

Natural killer cell dysregulation in polycystic ovary syndrome: immunometabolic and reproductive implication

Natural killer cells appear altered in PCOS, with mixed evidence

Key Findings

Interpretation

RRM Context

Abstract

Read the guide

Topics

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Keywords