Saini, P.; Mirji, G.; Bhat, S. A.; Muthumani, K.; Cassel, J.; Tang, H.-Y.; Tateno, H.; Zhang, R.; Shinde, R.; Abdel-Mohsen, M.

Tumor-associated macrophages (TAMs) in the tumor microenvironment exhibit impaired phagocytic activity, contributing to tumor progression. Here, we identify integrin 3{beta}1, composed of ITGA3 and ITGB1 subunits, as a sialylated glycoprotein ligand for Siglec-10, an inhibitory receptor on TAMs in pancreatic ductal adenocarcinoma (PDAC). Mechanistically, the interaction between Siglec-10 on TAMs and 3{beta}1 on PDAC cells suppresses macrophage-mediated phagocytosis, enabling immune evasion by PDAC. Consequently, disrupting Siglec-10 interactions with monoclonal antibodies significantly enhances macrophage phagocytosis of PDAC cells in vitro. In a PDAC xenograft mouse model engrafted with human macrophages, disrupting Siglec-10 interactions reduces tumor growth and activates the PI3K/MAPK/AP-1 signaling cascades in macrophages, enhancing their phagocytic capacity. These findings suggest that the interaction between Siglec-10 and integrin 3{beta}1 is a key mediator of immune evasion by TAMs and highlight the therapeutic potential of targeting Siglec-10/3{beta}1 interactions to restore macrophage phagocytic capacity.