Natural killer cell-mediated immunosurveillance modulates liver cancer evolution through cancer stemness enhancement and lipid metabolism reprogramming

Tumor evolution enables liver cancer cells to acquire survival advantages and evade therapy-induced cell death. However, the role of natural killer (NK) cells in liver cancer evolution remains unclear. Here, we establish immune-humanized spatiotemporal liver cancer models and integrate single-cell, spatial transcriptomic, and CRISPR/Cas9 screening analyses to investigate this process. We demonstrate that early NK cell-mediated immunosurveillance promotes tumor cell state transition and impairs subsequent adaptive immune responses. Mechanistically, NK cells induce lipid metabolic reprogramming, particularly cholesterol accumulation, and enhance tumor stemness, both of which promote liver cancer evolution. Furthermore, combined anti-LAG-3 treatment and liver X receptor activation suppress tumor evolution and improve the efficacy and durability of immune checkpoint blockade in advanced liver cancer. Collectively, our findings identify that NK cell-mediated early immunosurveillance promotes liver cancer evolution and suggest immunometabolic therapy as a potential strategy for advanced liver cancer. NK cell function in liver cancer has been shown and may influence the progression of liver cancer. Here the authors use mouse liver cancer models and spatial transcriptomics in an immune-humanized liver cancer mouse model to show that NK cells can influence the early progression of liver cancer by altering lipid metabolism and tumour stemness, subsequently demonstrating that inhibition of these pathways can enhance immune cell-mediated tumour control.