CTSE inhibits anti-tumor T cell response by promoting des-γ-carboxy prothrombin releasing in hepatocellular carcinoma.

The interactions between cancer cells and immune cells are crucial regulatory factors in forming the immuno-suppressive microenvironment. However, the underlying regulatory mechanisms remain elusive. In this study, we analyzed hepatocellular carcinoma (HCC) single-cell sequencing of public databases to investigate cellular interactions, revealing that cathepsin E (CTSE) highly expressed cancer cells exhibited significant interactions with T cells. Moreover, lower expression of CTSE is associated with an increased intra-tumoral CD3+ T cell infiltration. Mechanistically, CTSE highly expressed cancer cells upregulated the ubiquinone signaling pathway, enhancing the synthesis and release of des-γ-carboxy prothrombin (DCP), which subsequently activates reactive oxygen species (ROS) production and leads to apoptosis of Jurkat T cells. In vivo, animal experiments show that CTSE knockdown inhibited peripheral blood DCP levels and tumor growth while significantly enhancing the effectiveness of anti-PD-1 immunotherapy. Overall, our data reveal a regulatory mechanism involving CTSE-mediated DCP release and underscore the potential of CTSE knockdown in enhancing anti-PD-1 treatment. Cancer cells with high expression of CTSE upregulate the ubiquinone signaling pathway, promoting the synthesis and release of Des-γ-carboxyprothrombin (DCP). DCP can not only inhibit CD45+ and CD3+ immune infiltration, but also promote T cells to increase the production of reactive oxygen species (ROS), which leads to the increase of T cell apoptosis. CTSE knockdown can inhibit DCP levels and tumor growth, while significantly enhancing the effectiveness of anti-PD-1 immunotherapy.