Lysine metabolism reprogramming reshapes the immune microenvironment and induces immunotherapy tolerance in liver cancer

Liver cancer is one of the most common malignant tumors worldwide, and its high aggressiveness and recurrence rate pose a major challenge. Metabolic reprogramming is one of the cancer hallmarks and allows tumor cells to adapt to drastic changes, supporting their rapid growth, survival, and proliferation under various conditions. The metabolic reprogramming of several amino acids within tumors profoundly affects the function of the immune cells. Furthermore, arginine and various other amino acids are now being widely studied as potential targets for anti-tumor therapy. However, the role of lysine metabolic reprogramming in tumors remains largely unexplored. This study aims to reveal the relationship between lysine metabolism reprogramming and the prognosis of liver cancer, the tumor immune microenvironment (TIME), and responses to immunotherapy through multi-omics analysis. Combined transcriptomic and proteomic analyses revealed a significant downregulation of lysine metabolism in tumor tissues against normal tissue adjacent to the tumor from liver cancer patients. Subsequently, we constructed a lysine metabolism score (LM score) based on nine lysine metabolic genes to stratify liver cancer patients into high and low lysine metabolism subtypes. The LM score exhibited potential in predicting both survival and immunotherapy response in liver cancer. Furthermore, significant differences were observed in prognosis, clinical staging, TIME, and immunotherapy outcomes between the subtypes with low and high lysine metabolism. In the subtype of low lysine metabolism, an immunosuppressive TIME predominated, correlating with poorer patient survival and anti-tumor immune responses. In conclusion, we uncover that disturbed lysine metabolism promotes the formation of the immunosuppressive TIME, thereby inducing immunotherapy resistance and advancing liver cancer progression. This provides an effective theoretical reference for elucidating the mechanism of immunotherapy resistance in liver cancer and seeking new therapeutic strategies.