Multi-omics profiling reveals downregulated tumor lysine metabolism reshaping the immune microenvironment and therapeutic responses in hepatocellular carcinoma

Background: Hepatocellular carcinoma (HCC) is a major global health challenge with high aggressiveness and recurrence rates. Metabolic reprogramming is a cancer hallmark, enabling tumor cells to sustain rapid growth and evade immune surveillance. Several amino acids have been found to undergo metabolic reprogramming in tumors, and thus are potential anti-tumor targets. However, the characterization and implication of lysine metabolic reprogramming in HCC remain largely unexplored. Methods: We performed multi-omics profiling, including transcriptomics, proteomics, single-cell omics, immunohistochemistry, and multiplex immunofluorescence on tumor and adjacent normal tissues obtained from 30 HCC patients. Integrative analyses and quantitative evaluations were carried out to characterize the lysine metabolism and investigate its implications for tumor progression, immune microenvironment, and immunotherapy responses. Results: Our analysis observed a significant downregulation of lysine metabolism in HCC, with inter-patient heterogeneity. Patients with low lysine metabolism in tumors exhibited worse prognoses and a predominance of immunosuppressive tumor immune microenvironment (TIME), characterized by increased infiltration of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and exhausted CD8⁺ T cells (TIM3⁺CD8⁺ and LAG3⁺CD8⁺). These immunosuppressive cells contribute to immunotherapeutic resistance and promote tumor progression. Notably, our conclusions were consistently supported by observations at both the bulk and single-cell resolutions, as well as T cell receptor (TCR) immune repertoire profiling, reinforcing the robustness of our findings. Conclusions: This study provides comprehensive evidence that lysine metabolism plays a critical role in shaping the immunosuppressive TIME in HCC and is associated with clinical outcomes and resistance to immunotherapy, offering new insights into clinical molecular subtyping and potential therapeutic strategies.