Bulk and Single-Cell Transcriptomes Reveal Exhausted Signature in Prognosis of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a highly heterogeneous malignancy with poor prognosis. T cell exhaustion (TEX) is a key factor in tumor immune evasion and therapeutic resistance. In this study, we integrated single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing (RNA-seq) data to characterize TEX-related transcriptional features in HCC.

We first computed TEX scores for each sample using a curated 65-gene signature and classified them into high-TEX and low-TEX groups by the median score. Differentially expressed genes were identified separately in scRNA-seq and bulk RNA-seq data, then intersected to retain shared candidates. A 26-gene prognostic signature was derived from these candidates via univariate Cox and LASSO regression analysis.

The high-TEX group exhibited increased expression of immune checkpoint molecules and antigen presentation molecules, suggesting a tumor microenvironment that is more immunosuppressive but potentially more responsive to immunotherapy. Functional enrichment analysis and protein-protein interaction (PPI) network construction further validated the roles of these genes in immune regulation and tumor progression.

This study provides a comprehensive characterization of the TEX landscape in HCC and identifies a robust gene signature associated with prognosis and immune infiltration. These findings highlight the potential of targeting TEX-related genes for personalized immunotherapeutic strategies in HCC.