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

  • NPJ Precis Oncol. 2025 Dec 15;9(1):398. doi: 10.1038/s41698-025-01169-0.
Kuan-Yu Lin  #  1 ,  Jeng-Kai Jiang  #  2  3 ,  Jui-I Lai  1 ,  Si-Yun Lin  1 ,  Yu-Chang Ku  1 ,  Miao-Hsia Lin  1 ,  Chih-Yung Yang  4  5 ,  Liang-Chuan Lo  6 ,  Tsui-Ling Hsu  7 ,  Yung-Chi Chang  8
Affiliations
  • 1. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan.
  • 2. School of Medicine, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan.
  • 3. Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, 112304, Taiwan.
  • 4. General Education Center, University of Taipei, Taipei, 100234, Taiwan.
  • 5. Department of Education and Research, Taipei City Hospital, Taipei, 10629, Taiwan.
  • 6. Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, 112304, Taiwan.
  • 7. Genomics Research Center, Academia Sinica, Taipei, Taiwan.
  • 8. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan. [email protected].
  • # Contributed equally.
PMID: 41398201 DOI: 10.1038/s41698-025-01169-0
Abstract

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.

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