Longitudinal scRNA-seq analysis reveals molecular features of T cell exhaustion linked to anti-PD-1 response in hepatocellular carcinoma

The efficacy of immune checkpoint blockade in hepatocellular carcinoma remains suboptimal, characterized by low objective response rates. Given that the tumor microenvironment plays a pivotal role in determining immune checkpoint blockade effectiveness, a comprehensive understanding of its molecular and cellular dynamics before and after immune checkpoint blockade treatment is crucial. In this study, we conducted single-cell RNA sequencing on fourteen tumor biopsies and eight blood samples obtained from ten hepatocellular carcinoma patients before and after anti-PD-1 therapy, including four paired samples. Our analysis revealed that differential therapeutic responses were associated with distinct T cell states and a progenitor-to-terminal exhaustion trajectory. Developmental trajectory analysis identified key genes implicated in T cell exhaustion and validated the molecular signatures indicative of pro-exhaustion across experimental models. Furthermore, we observed a correlation between T cell exhaustion and malignant epithelial cells. These findings provide important insights into potential strategies for enhancing immunotherapy in advanced hepatocellular carcinoma by targeting T cell exhaustion.