Targeting Siglec-10/α3β1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer
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Tumor-associated macrophages (TAMs) in the tumor microenvironment exhibit impaired phagocytic activity, contributing to tumor progression. Here, we identify integrin α3β1, 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 α3β1 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 α3β1 is a key mediator of immune evasion by TAMs and highlight the therapeutic potential of targeting Siglec-10/α3β1 interactions to restore macrophage phagocytic capacity.
