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<p>Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). 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.</p>

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Targeting ST3GAL1 to downregulate ligands for the glycoimmune checkpoint Siglec-7 and reverse immune escape in hepatocellular carcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Tan-chi Fan,
  • Tsai-Hsien Hung,
  • Chau-Ting Yeh,
  • Po-Ting Lin,
  • Nai-Chuan Chang,
  • Tzu-Chi Lo,
  • Tsai-Jung Wu,
  • John Yu,
  • Alice L. Yu

摘要

Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). 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.