Authors
Jiongming He, Shan Liu, Lingying Wang, Fei Xiong
Published in
Journal of leukocyte biology. Aug 26, 2026. Epub Aug 26, 2026.
Abstract
Natural killer (NK) cells are active tumoricidal cells that inhibit esophageal cancer (EC) development, making them a prospective immunotherapeutic tool. Nonetheless, NK cells undergo both activation and exhaustion in the tumor microenvironment, but the related mechanisms have not been thoroughly understood. Using a chemical-induced EC model, we investigated the expression pattern and functional properties of zinc finger protein 600 (ZNF600) in EC-associated NK cells. For the first time, we revealed that ZNF600 expression was diminished in EC-associated NK cells, particularly those exhibiting the exhaustion phenotype. In vitro silencing of ZNF600 resulted in a remarkable downregulation of tumor necrosis factor (TNF), interferon-gamma (IFN-γ), and cytolytic perforin and granzyme B, leading to an impairment of NK cell tumoricidal capacity. On the contrary, ZNF600 overexpression promoted NK cell tumoricidal capacity. Adoptive transfer of ZNF600-overexpressing NK cells significantly inhibited the growth of EC implants. Furthermore, EC cells significantly down-regulated ZNF600 in NK cells. Interestingly, neutralizing carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) partially restored ZNF600 expression after co-culture with EC cells. Conclusively, the CEACAM1-TIM-3 signaling axis might decrease ZNF600 in EC-associated NK cells and subsequently suppress NK cell-mediated killing of EC cells. This research discovers a novel mechanism by which the EC microenvironment induces NK cell dysfunction.
PMID:
42647748
Bibliographic data and abstract were imported from PubMed on 27 Aug 2026.
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