Ammonia Detoxification Inhibits Liver Metastasis by Reshaping Hepatic Microenvironment

Liver metastases represent an urgent unmet medical need in the care of cancer due to a lack of effective therapies. This study reveals that pathological ammonia accumulation, resulting from dysregulation of ammonia removal processes, promotes the formation of a hepatic microenvironment favorable for metastatic colonization. Metabolomic and transcriptomic analyses suggest that tumoral metabolic reprogramming due to cancer cell-intrinsic hyperactivation of the de novo pyrimidine biosynthesis pathway impairs the urea cycle and causes pathological ammonia accumulation. Utilizing tumor microenvironmental profiling and single-cell RNA sequencing, subsequent analyses further reveal that ammonia accumulation remodels the hepatic stromal-immune landscape by inducing hepatic stellate cell differentiation into metastasis-associated fibroblasts (MAFs), suppressing Ifi27l2a⁺ monocyte-macrophages, and expanding pro-metastatic low-density neutrophils (LDNs). Strikingly, the ammonia detoxifying agent L-ornithine-L-aspartate (LOLA) potently promotes ammonia removal, thereby reshaping the hepatic microenvironment with decrease of MAFs and LDNs and increase of Ifi27l2a⁺ monocyte-macrophages, and reducing metastatic burden in liver metastasis mouse models. These results suggest that ammonia, a metabolic toxin, is required for the formation of the hepatic microenvironment favoring liver metastatic colonization, and highlight LOLA as a promising therapeutic strategy for treatment of liver metastasis by detoxifying pathological ammonia accumulation.