Siglec-14-LGALS3BP glycoimmune axis shapes tumor-associated macrophage polarization and confers poor outcome in colorectal cancer

Colorectal Cancer (CRC) is a leading cause of cancer-related deaths, particularly in metastatic cases. Sialic acid, frequently overexpressed in tumors, promotes immune evasion by engaging Siglecs (Sialic acid-binding immunoglobulin-like lectins) on immune cells. Siglec-5 and Siglec-14, expressed on myeloid cells, share ligand-binding domains but have opposing signaling functions. While these paired receptors regulate macrophage immune responses against Bacterial infection, their role in the tumor microenvironment remains unclear. We found that Siglec-14 expression in THP-1 macrophages, when exposed to CRC tumor-conditioned medium, induces a protumoral SPP1⁺ tumor-associated macrophage phenotype, with enrichment of angiogenic pathways. In vivo, Siglec-14-expressing macrophages promoted CRC xenograft growth in mice, and their conditioned medium enhanced angiogenesis in chicken chorioallantoic membranes. We identified LGALS3BP (Lectin galactoside-binding soluble 3 binding protein), a sialylated glycoprotein in CRC tumor-conditioned medium, as a Siglec-14 ligand. Blocking this interaction reduced tumor-associated macrophage polarization and VEGF release. Siglec-14 is absent in some individuals due to a SIGLEC5/14 fusion polymorphism. Siglec-14-positive CRC patients exhibited elevated serum LGALS3BP, which correlated with advanced progression and poorer survival. Collectively, these findings establish the LGALS3BP-Siglec-14 axis as a potential therapeutic target, offering a strategy to enhance antitumor immunity in Siglec-14-positive CRC patients.