Integrative profiling of liver cancer reveals lysine metabolic reprogramming and patient stratification with distinct immune microenvironment and therapeutic responses

Liver cancer is a major global health challenge with high aggressiveness and recurrence rate. 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. Several amino acids have been found to undergo metabolic reprogramming in tumors and thus being potential anti-tumor targets. However, the characterization and implication of lysine metabolic reprogramming in tumors remains largely unexplored. Therefore, we carried out transcriptomics, proteomics, single-cell omics, immunohistochemistry, and multiplex immunofluorescence profiling on tumor and adjacent normal tissues obtained from 30 hepatocellular carcinoma patients to characterize the lysine metabolism in liver cancer and investigate its implications for tumor prognosis, immune microenvironment, and immunotherapy responses. Integrative analyses and quantitative evaluations revealed the reprogrammed lysine metabolism and inter-patient heterogeneity in liver cancer. The patients with lower lysine metabolism in tumors had worse prognoses and a predominance of immunosuppressive TIME, including increased infiltration of myeloid-derived suppressor cells, Tregs, TIM3+CD8+, and LAG3+CD8+T cells. These immunosuppressive cells contribute to immunotherapeutic resistance and promote tumor progression. Collectively, we highlighted the significance of lysine metabolism in shaping TIME and therapeutic responses of liver cancer, offering new insights into clinical molecular subtyping and potential therapeutic strategies. Overall design: We performed scRNA-seq on tumor and adjacent tissues from four pairs of hepatocellular carcinoma patients using the 10x Genomics platform, and one pair of samples also underwent scTCR-seq.