Zinc finger protein 600 is essential for the cytotoxic function of esophageal cancer-associated natural killer cells

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.