Wan Yejian, Geng Xiaoxia, Liu Qianshi, Lu Shaolong, Liu Yiqiang, Wang Tao, Zhang Xingmei, Li Na, Li Dongyun, Li Zhaoshen, Liu Junjie, Wu Hong, Chen Jie
Department of Hepatobiliary Surgery, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China.
Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Cell Death Dis. 2025 Jun 4;16(1):434. doi: 10.1038/s41419-025-07753-3.
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.
癌细胞与免疫细胞之间的相互作用是形成免疫抑制微环境的关键调节因子。然而，其潜在的调节机制仍不清楚。在本研究中，我们分析了公共数据库中的肝细胞癌（HCC）单细胞测序以研究细胞间相互作用，发现组织蛋白酶E（CTSE）高表达的癌细胞与T细胞表现出显著的相互作用。此外，CTSE表达较低与肿瘤内CD3+ T细胞浸润增加有关。机制上，CTSE高表达的癌细胞上调泛醌信号通路，增强去γ-羧基凝血酶原（DCP）的合成与释放，随后激活活性氧（ROS）生成并导致Jurkat T细胞凋亡。在体内，动物实验表明，敲低CTSE可抑制外周血DCP水平和肿瘤生长，同时显著增强抗PD-1免疫治疗的效果。总体而言，我们的数据揭示了一种涉及CTSE介导的DCP释放的调节机制，并强调了敲低CTSE在增强抗PD-1治疗方面的潜力。CTSE高表达的癌细胞上调泛醌信号通路，促进去γ-羧基凝血酶原（DCP）的合成与释放。DCP不仅可抑制CD45+和CD3+免疫浸润，还可促进T细胞增加活性氧（ROS）生成，从而导致T细胞凋亡增加。敲低CTSE可抑制DCP水平和肿瘤生长，同时显著增强抗PD-1免疫治疗的效果。
