Pancreatic cancer-associated fibroblasts (CAFs) modulate macrophage differentiation via sialic acid-Siglec interactions. Despite advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains resistant due to an immunosuppressive tumor microenvironment, characterized by the abundance of CAFs. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are overexpressed by cancer cells. This study reveals a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, it was shown that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. Sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, these findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC. The PDAC tumor microenvironment is unique in its abundance of dense fibrotic stroma and suppressive immune cells. The stroma in PDAC can constitute up to 80% of the tumor mass and comprises of extracellular matrix and specialized connective-tissue cells, including CAFs. CAFs are highly heterogeneous in their phenotypes, origins and functions, including both tumor-promoting and tumor-inhibiting properties. Advances in single-cell technologies have led to the identification of several CAF subsets in PDAC that include inflammatory CAFs (iCAF), myofibroblastic CAFs (myCAF) and antigen-presenting CAFs (apCAF). Immune cells in the TME are mainly of the myeloid lineage, the majority being tumor-associated macrophages (TAMs). Accumulation of TAMs correlates with poor prognosis of PDAC. TAMs are chronically polarized by the tumor and show a mixed phenotype of both anti-tumoral and pro-tumoral activation states, marked by the expression of HLA-DR and CD86 or CD163, CD206 and PD-L1, respectively. Besides the role of TAMs in tissue remodeling and inflammation, TAMs induce immunosuppression in the TME by recruiting Tregs and inhibiting CD8+ T and NK cell cytPancreatic cancer-associated fibroblasts (CAFs) modulate macrophage differentiation via sialic acid-Siglec interactions. Despite advances in cancer immunotherapy, pancreatic ductal adenocarcinoma (PDAC) remains resistant due to an immunosuppressive tumor microenvironment, characterized by the abundance of CAFs. Siglec receptors are increasingly recognized as immune checkpoints, and their ligands, sialic acids, are overexpressed by cancer cells. This study reveals a previously unrecognized role of sialic acid-containing glycans on PDAC CAFs as crucial modulators of myeloid cells. Using multiplex immunohistochemistry and transcriptomics, it was shown that PDAC stroma is enriched in sialic acid-containing glycans compared to tumor cells and normal fibroblasts, and characterized by ST3GAL4 expression. Sialic acids on CAF cell lines serve as ligands for Siglec-7, -9, -10 and -15, distinct from the ligands on tumor cells, and these receptors are found on myeloid cells in the stroma of PDAC biopsies. Furthermore, CAFs drive the differentiation of monocytes to immunosuppressive tumor-associated macrophages in vitro, and CAF sialylation plays a dominant role in this process compared to tumor cell sialylation. Collectively, these findings unravel sialic acids as a mechanism of CAF-mediated immunomodulation, which may provide targets for immunotherapy in PDAC. The PDAC tumor microenvironment is unique in its abundance of dense fibrotic stroma and suppressive immune cells. The stroma in PDAC can constitute up to 80% of the tumor mass and comprises of extracellular matrix and specialized connective-tissue cells, including CAFs. CAFs are highly heterogeneous in their phenotypes, origins and functions, including both tumor-promoting and tumor-inhibiting properties. Advances in single-cell technologies have led to the identification of several CAF subsets in PDAC that include inflammatory CAFs (iCAF), myofibroblastic CAFs (myCAF) and antigen-presenting CAFs (apCAF). Immune cells in the TME are mainly of the myeloid lineage, the majority being tumor-associated macrophages (TAMs). Accumulation of TAMs correlates with poor prognosis of PDAC. TAMs are chronically polarized by the tumor and show a mixed phenotype of both anti-tumoral and pro-tumoral activation states, marked by the expression of HLA-DR and CD86 or CD163, CD206 and PD-L1, respectively. Besides the role of TAMs in tissue remodeling and inflammation, TAMs induce immunosuppression in the TME by recruiting Tregs and inhibiting CD8+ T and NK cell cyt