Siglec-15 Regulates the Inflammatory Response and Polarization of Tumor-Associated Macrophages in Pancreatic Cancer by Inhibiting the cGAS-STING Signaling Pathway

Tumor-associated macrophages especially M2 phenotype macrophages play an important role in tumor progression and the formation of immunosuppressive tumor microenvironment. Previous studies indicated that infiltration of a large number of M2-macrophages was positively associated with a low survival rate and poor prognosis of patients with pancreatic ductal cancer. However, the mechanisms responsible for M2-macrophage polarization remain unclear. Recently, Siglec-15 appears as an emerging target for the normalization of the tumor immune microenvironment. Hence, we detected the Sigelc-15 expression on macrophages by using qPCR and Western blot assay and found that the expression of Siglec-15 was upregulated on M2 macrophages induced by IL-4 and conditioned media from pancreatic ductal cancer. In addition, after knocking out Siglec-15, the expression of M2 phenotype macrophage biomarkers such as Arg1 and CD206 was significantly downregulated. Besides, in our study we also found that Siglec-15 could upregulate the glycolysis of macrophage possibly by interacting with Glut1 to regulate the M2-macrophage polarization. The regulation was also partly dependent on STING, and Glut1-related glycose metabolism was involved in regulating cGAS/STING signaling. When utilizing a subcutaneous transplantation mouse model, we observed that knocking out of Siglec-15 or co-injecting tumor cells with macrophage from Siglec-15 KO mice could significantly inhibit the growth of subcutaneous tumors in mice. Taken together, these findings suggest that Siglec-15 is essential for the M2-macrophage polarization to shape an immune suppressive tumor microenvironment in pancreatic cancer and makes it an attractive target for pancreatic cancer immunotherapy.