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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290298 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description: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.

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

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