This study identifies Siglec-10 as a dominant inhibitory glyco-immune checkpoint on tumor-associated macrophages (TAMs) in pancreatic ductal adenocarcinoma (PDAC) and demonstrates that PDAC cells evade innate and adaptive immunity by exploiting sialylated integrin \u03b13\u03b21 (ITGA3\u2013ITGB1) as a functional ligand for Siglec-10. Mechanistically, \u03b13\u03b21 on PDAC cells is heavily sialylated, enabling high-affinity engagement of Siglec-10 on TAMs, which triggers inhibitory signaling through ITIM motifs, suppresses macrophage phagocytosis, skews TAMs toward an immunosuppressive phenotype, and indirectly dampens T-cell proliferation and activation via myeloid-mediated suppression. Antibody-mediated blockade of Siglec-10 disrupts this glycan-dependent interaction, restores macrophage phagocytic capacity against PDAC cells, relieves suppression of T-cell responses in vitro, and significantly reduces tumor growth in both human macrophage\u2013engrafted xenograft models and human Siglec-10 transgenic mice. Collectively, the work establishes the Siglec-10\u2013\u03b13\u03b21 axis as a critical macrophage checkpoint driving immune evasion in PDAC and positions Siglec-10 blockade as a promising immunotherapeutic strategy to reprogram the PDAC tumor microenvironment toward antitumor immunity.<\/p>\n\n\n\n