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

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.