The dual roles of natural killer cells in liver immunity and tolerance: Implications for health and disease

The liver, a pivotal organ in immunity, functions as a central site with dual roles in immune defense and tolerance. Natural killer (NK) cells, a key subset of hepatic lymphocytes, display significant heterogeneity, with varied phenotypic and functional traits that enable them to perform essential roles in immune surveillance, maintain tissue homeostasis, and defend against pathogens and tumors. NK cell activation is tightly controlled by a balance between activating and inhibitory receptors, which orchestrates their cytotoxic, cytokine-producing, and immunoregulatory functions. They are vital participants in antiviral responses, tumor surveillance, fibrosis regulation, and liver regeneration. In chronic liver diseases such as viral hepatitis, fibrosis, and hepatocellular carcinoma (HCC), NK cell dysfunction, characterized by diminished cytotoxic function and altered receptor expression, contributes to disease progression. Emerging therapies, including chimeric antigen receptor-engineered NK (CAR-NK) cells and cytokine-based treatments, aim to restore NK cell functionality and harness their therapeutic potential for liver disease management. This review highlights the dual roles of NK cells in liver health and disease, emphasizing their significance in immune regulation, disease progression, and therapeutic innovation.