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

Tan-Chi Fan1, Tsai-Hsien Hung2, Chau-Ting Yeh2,3

  • 1Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan. b821615@life.nthu.edu.tw.

Cancer Immunology, Immunotherapy : CII
|April 10, 2026
PubMed

Insights

Sorafenib resistance in liver cancer is linked to altered cell surface sugars that shield tumors from natural killer (NK) cells. Targeting ST3GAL1 may restore NK cell anti-tumor activity.

Area of Science:

  • Immunology
  • Oncology
  • Glycobiology

Background:

  • Sorafenib is a first-line treatment for advanced hepatocellular carcinoma (HCC), but acquired resistance is a major clinical hurdle.
  • Sorafenib treatment alters O-glycans in HCC cells, yet the link between these glycosylation changes and therapy resistance is not fully understood.
  • Natural killer (NK) cells express glycoimmune checkpoints Siglec-7 and Siglec-9, which interact with ligands on target cells.

Purpose of the Study:

  • To investigate the role of sorafenib-induced glycosylation changes in HCC immune escape.
  • To determine the impact of ST3GAL1 on Siglec-7/9 ligand expression and NK cell cytotoxicity in HCC.
  • To explore the therapeutic potential of targeting ST3GAL1 in HCC.

Main Methods:

  • Analysis of Siglec-7/9 ligand expression on HCC cells and their interaction with NK cells.
  • Silencing of ST3GAL1 in liver cancer cells to assess effects on NK cell and antibody-dependent cellular cytotoxicity (ADCC).
  • Correlation of ST3GAL1 expression with clinical outcomes in HCC patients.

Main Results:

  • Sorafenib-resistant HCC cells exhibit hypersialylation, increasing Siglec-7/9 ligands and evading NK cell attacks.
  • ST3GAL1 silencing reduced Siglec-7 ligands, making cancer cells more vulnerable to NK cell and cetuximab-induced ADCC.
  • High ST3GAL1 expression is linked to poor clinical outcomes in early-stage HCC patients.

Conclusions:

  • ST3GAL1 plays a key role in HCC immune evasion by modulating Siglec-7 ligands and protecting against NK cell cytotoxicity.
  • Elevated ST3GAL1 expression is a biomarker for adverse outcomes in HCC.
  • Targeting ST3GAL1 offers a potential strategy to enhance NK cell-mediated anti-tumor immunity in HCC.
Keywords:
ADCCImmunotherapyNKSialylationSialyltransferaseSiglec

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