Targeting SYK to alleviate MDSC-driven immunosuppression and augment anti-PD1 efficacy.
Zeng Z., Cao X., Li C., He Y., Guo H., Cao X., Gong T., Sun J., Hu Y., Hu Z., Lai Y., Zhang D., Warner N., Uhlig HH., Li Q., Muise AM., Tan Y., Huang Y., Deng L., Deng L., Sun Z., Zhong M., Zhang X., Li D.
Myeloid-derived suppressor cells (MDSCs) play a crucial role in tumor-associated immune suppression and in impeding immune checkpoint blockade (ICB) therapies; however, effective intervention strategies targeting MDSCs remain limited. In this study, we observed a positive correlation between spleen tyrosine kinase (SYK) activity in immune cells and tumor progression in human cancers. Utilizing a mouse model with a gain-of-function SYKS544Y mutation, we demonstrated that SYK activation promotes tumorigenesis in carcinogen-induced and xenograft models across multiple cancer types, largely through MDSC-dependent mechanisms. Mechanistically, SYK activates the JAK-STAT-CXCR2 signaling axis, enhancing MDSC migration and suppressing antitumor T cell responses. Notably, pharmacological inhibition of SYK not only inhibited tumor growth but also enhanced the therapeutic effect of anti-PD-1 in mouse models and patient-derived tumor organoid models. Our findings highlight the immunoregulatory role of SYK in tumor progression and suggest that targeting SYK represents a promising strategy to remodel the tumor microenvironment and enhance the efficacy of checkpoint blockade immunotherapy.