Background: Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with a rising prevalence worldwide. Immunotherapy has been shown to improve treatment outcomes for HCC. We aimed to construct a T-cell exhaustion-related gene prognostic model (TEXPM) for HCC and to elucidate the immunologic characteristics and advantages of immunotherapy in T-cell exhaustion-Related Gene-defined HCC groups.

Methods: Single-cell RNA sequencing data were used in conjunction with TCGA Differentially expressed genes (DEGs) to screen for T-cell exhaustion-Related Genes (TEXGs) for subsequent evaluation. Using univariate Cox regression analysis and LASSO regression analysis, five genes (FTL, GZMA, CD14, NPC2, and IER3) were subsequently selected for the construction of a TEXPM. Then, we evaluated the immunologic characteristics and advantages of immunotherapy in groups identified by TEXPM.

Results: The TEXPM was formed with FTL, GZMA, CD14, NPC2, and IER3. The results of the training and validation team studies were consistent, with the low TEXPM group surviving longer than the high TEXPM group (P < 0.001). Multivariate Cox regression analysis demonstrated that TEXPM (HR: 2.347, 95%CI: 1.844-2.987; HR: 2.172, 95% CI: 1.689-2.793) was an independent prognostic variable for HCC patients. The low-TEXPM group was linked to active immunity, less aggressive phenotypes, strong infiltration of CD8+ T cells, CD4 + T cells, and M1 macrophages, and a better response to ICI treatment. A high TEXPM group, on the other hand, was associated with suppressive immunity, more aggressive phenotypes, a significant infiltration of B cells, M0 macrophages, and M2 macrophages, and a reduced response to ICI treatment. FTL is an independent prognostic variable in HCC patients and the knockdown of FTL can affect the biological behavior of hepatocellular carcinoma cells.

Conclusions: TEXPM is a promising prognostic biomarker connected to the immune system. Differentiating immunological and molecular features and predicting patient outcomes may be facilitated by TEXPM grouping. Furthermore, the expression of FTL was found to be an independent prognostic factor for HCC. Knockdown of FTL significantly inhibited proliferation, migration, and invasive activity in liver cancer cells.