Fig. 2: Dysregulation of methionine recycling machinery leads to increasing tumor SAM and MTA content and drives T-cell exhaustion in HCC Tumor.

a The waterfall plot demonstrates the correlation between ES and the tumor-to-non-tumor level of different metabolites in HCC tumors of TIGER-LC cohort (Supplementary Table 5). b Schema of methionine recycling machinery. c Heatmap reveals the expressions of genes involving methionine recycling pathways (lower panel) and the associated tumor ES (upper panel) in HCC tumors. d The relationship of ES and the expressions of salvage pathway and de novo pathway in HCC tumors. (n = 62) Correlation coefficient and P values are based on two-sided Spearman’s rank correlation coefficient test. e The relationships of the tumor SAM and MTA contents with the salvage-to-de novo ratio. (n = 62) Correlation coefficient and P values are assessed by two-sided Spearman’s rank correlation coefficient test. f, g Single-cell transcriptomic study on HCC tumors validates the metabolic interaction linking cancer methionine metabolism and T-cell exhaustion. Single-cell transcriptome of malignant cells and associated T cells are obtained from four HCC patients (GEO125449, n = 534). We defined malignant cells as salvage-high or de novo-high by the mean value of the salvage-to-de novo ratio of all malignant cells. We then reconstructed each tumor according to the proportion of salvage-high (colored in red) or de novo-high (colored in orange) cancer (f, left panel). According to the dominant methionine metabolic status of HCC cells, tumors from P3 and P4 are defined as salvage-dominant tumors and P1 tumor is considered as de novo-dominant tumor. 175T cells associated with the above-mentioned tumors are identified. t-SNE plot showed the transcriptome differences among T cells originated from salvage-dominant tumors to de novo-dominant tumor (f, right panel). The expressions of T-cell exhaustion-specific genes, DNA methyltransferase genes, and methionine metabolic genes of T cells were examined and summarized using violin plots g. Statistical significance is determined by two-sided independent t test. Source data are provided as a Source Data file.