This study investigates the role of sialic acid-containing glycans on cancer-associated fibroblasts (CAFs) in modulating myeloid cell differentiation in pancreatic ductal adenocarcinoma (PDAC). The authors found that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, with ST3GAL4 expression being a key regulator. Sialic acids on CAFs serve as ligands for Siglec-7, -9, -10, and -15 receptors, which are present on myeloid cells in the tumor microenvironment. CAFs were shown to drive the differentiation of monocytes into immunosuppressive tumor-associated macrophages (TAMs) in vitro, with CAF-derived sialylation playing a dominant role compared to tumor cell sialylation. The study highlights the potential of targeting CAF-derived sialylation as a therapeutic strategy in PDAC.This study investigates the role of sialic acid-containing glycans on cancer-associated fibroblasts (CAFs) in modulating myeloid cell differentiation in pancreatic ductal adenocarcinoma (PDAC). The authors found that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, with ST3GAL4 expression being a key regulator. Sialic acids on CAFs serve as ligands for Siglec-7, -9, -10, and -15 receptors, which are present on myeloid cells in the tumor microenvironment. CAFs were shown to drive the differentiation of monocytes into immunosuppressive tumor-associated macrophages (TAMs) in vitro, with CAF-derived sialylation playing a dominant role compared to tumor cell sialylation. The study highlights the potential of targeting CAF-derived sialylation as a therapeutic strategy in PDAC.