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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<jats:sup>+<\/jats:sup> T cell infiltration. Mechanistically, CTSE highly expressed cancer cells upregulated the ubiquinone signaling pathway, enhancing the synthesis and release of des-\u03b3-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.<\/jats:p>","DOI":"10.1038\/s41419-025-07753-3","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:35:53Z","timestamp":1749036953000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["CTSE inhibits anti-tumor T cell response by promoting des-\u03b3-carboxy prothrombin releasing in hepatocellular carcinoma"],"prefix":"10.1038","volume":"16","author":[{"given":"Yejian","family":"Wan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianshi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaolong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqiang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingmei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongyun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoshen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4823-2348","authenticated-orcid":false,"given":"Jie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"7753_CR1","doi-asserted-by":"publisher","first-page":"1301","DOI":"10.1016\/S0140-6736(18)30010-2","volume":"391","author":"A Forner","year":"2018","unstructured":"Forner A, Reig M, Bruix J. 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For studies involving human subjects, before being included in this study, each human subject obtained written informed consent, and this study was approved by the Research Ethics Committee of Affiliated Cancer Hospital of Guangxi Medical University. All studies involving animals have been approved by the Animal Care and Use Committee of Guangxi Medical University and conducted in accordance with these approved guidelines (no. KY2022003).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}],"article-number":"434"}}