Recently, Prof. Ma Chunhong, Prof. Liu Xinyong and Prof. Han Bo's team published a research paper entitled "Increased Siglec-9/Siglec-9L interaction in NK cells predicts poor HCC prognosis and can be a targetable checkpoint for immunotherapy" in Journal of Hepatology (IF=25.7). Professor Ma Chunhong, Professor Liang Xiaohong from the School of Basic Medical SciencesofShandong University, Professor Liu Xinyong from the School of Pharmaceutical Sciences of Shandong University and Professor Han Bo from the Department of Pathology of Qilu Hospital of Shandong University are co-corresponding-authors. Doctoral candidate Xiao Rong and postdoctor TianYeare co-first authors. Shandong University is the first author's and corresponding author's affiliation.

Hepatocellular carcinoma (HCC) has a high incidence and mortality rate, making it the third leading cause of cancer-related deaths globally. In recent years, immune checkpoint inhibitors (ICIs) have brought revolutionary breakthroughs in the treatment of liver cancer, but the overall response rate is low, and they are prone to immune-related adverse reactions in multiple organs throughout the body. Therefore, it is necessary to further explore and find better immune checkpoint targets and drugs for the treatment of liver cancer. NK cells have strong cytotoxic activity against tumour cells and are abundant in the liver. Siglec-7 and Siglec-9 are two emerging immune checkpoints mainly expressed in human NK cells, but their spatial interaction networks in the HCC microenvironment and their potential as therapeutic targets remain unclear.

The research team found that Siglec-9 and Siglec-9L were significantly overexpressed in TINK and negatively correlated with prognosis. Further analysis revealed that there was a stronger interaction between Siglec-9+ NK cells and Siglec-9L+ NK cells in tumour tissues. However, Siglec-7 and its ligands did not participate in regulating the occurrence and development of liver cancer. The above results suggest that Siglec-9/Siglec-9L can be used as a potential intervention target for liver cancer immunotherapy in NK cells. Next, the research team screened out a small molecule compound MTX-3937 that binds to Siglec-9 from 306,709 small molecule compounds. In vitro and in vivo experiments confirmed that MTX-3937 enhanced NK cell anti-tumour immunity by inhibiting the Siglec-9 signaling pathway, and promoted NK cell homeostasis, indicating that MTX-3937 can be used as a lead compound with clinical application prospects for HCC immunotherapy. These results provide the rationale for HCC treatment by targeting Siglec-9 on NK cells.

Professor Ma Chunhong's team has been committed to basic and intervention strategies for the development of liver-related diseases. Professor Liu Xinyong’s team has been committed to novel drug discovery based on the combination of target structure and multiple medicinal chemistry strategies. They have achieved a series of high-level research outcomes. This work was supported by the National Key Research and Development Program of China, National Natural Science Foundation of China, Taishan Scholarship, Shandong Natural Science Foundation, Shandong Laboratory Program and Advanced Medical Research Institute.