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However, acquired resistance to sorafenib remains a significant challenge. Previous studies have shown that sorafenib treatment induces the formation of truncated O-glycans in HCC cells, but the relationship between sorafenib-induced glycosylation changes and acquired therapy resistance remains unclear. Primary natural killer (NK) cells, freshly isolated from peripheral blood or following culture and expansion, expressed the glycoimmune checkpoints Siglec-7 and Siglec-9. HCC cells exhibited varying levels of Siglec-7\/9 ligands on their surface. Sorafenib-resistant liver cancer cells displayed hypersialylation, leading to increased expression of surface Siglec-7\/9 ligands, which conferred protection against NK cell-mediated cytotoxicity. Silencing ST3GAL1 significantly reduced Siglec-7 ligand expression on liver cancer cells, enhancing their susceptibility to NK-mediated cytotoxicity and cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) in epidermal growth factor receptor (EGFR)-expressing tumor cells. Furthermore, high ST3GAL1 expression correlated with poor clinical outcomes in patients with stage 1-2 HCC. This study highlights the critical role of ST3GAL1 in regulating Siglec-7 ligands to facilitate immune escape from NK cell cytotoxicity. Moreover, its elevated expression is associated with adverse clinical outcomes in HCC. Targeting ST3GAL1 may represent a promising strategy to enhance NK cell-mediated anti-tumor immunity in HCC.<\/jats:p>","DOI":"10.1007\/s00262-026-04388-x","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T14:14:05Z","timestamp":1775830445000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting ST3GAL1 to downregulate ligands for the glycoimmune checkpoint Siglec-7 and reverse immune escape in hepatocellular carcinoma"],"prefix":"10.1007","volume":"75","author":[{"given":"Tan-chi","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Hsien","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chau-Ting","family":"Yeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Po-Ting","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nai-Chuan","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Chi","family":"Lo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsai-Jung","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice L.","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,10]]},"reference":[{"key":"4388_CR1","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s00210-019-01711-5","volume":"393","author":"TJ Fan","year":"2020","unstructured":"Fan TJ, Wu SX, Jiang GJ (2020) Apoptotic effects of Norfloxacin on corneal endothelial cells. 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