Siglecs: From Biomodulation to Immunotherapy

BACKGROUND: Sialic acid-binding immunoglobulin-like lectins (Siglecs) are cell-surface immunological receptors predominantly expressed on immune cells such as monocytes, macrophages, and dendritic cells. They play a crucial role in regulating inflammatory processes in various diseases and serve as immunological checkpoints in cancer. Despite several immune checkpoint inhibitors targeting Siglecs having entered clinical trials, the number of Siglec-targeted immunotherapies remains limited. OBJECTIVE: This review aims to investigate the contributions of Siglecs in human diseases and explore novel therapeutic strategies targeting the Siglec-sialic acid immunological axis. METHODS: The authors systematically searched PubMed, Web of Science, and Google Scholar for publications mainly from 2015-2025, using search terms related to Siglecs, tumors, autoimmune diseases, and specific Siglec subtypes (CD169, Siglec2). Studies were included if they examined Siglecs biology, immunomodulation, or immunotherapeutic potential. Studies not directly relevant to Siglecs function/therapeutics and non-peer-reviewed materials (conference abstracts, editorials) were excluded. Screening was done via titles and abstracts with data referenced from research article results, and eligible articles underwent full-text review for final inclusion. RESULTS: The analysis reveals that Siglecs exhibit dual functions, acting as both activators and inhibitors of immune responses. They are implicated in the pathogenesis of various diseases, including cancer, autoimmune disorders, and viral infections. Several Siglec-targeted immunotherapies are currently in clinical trials, demonstrating their potential in disease management. For instance, Siglec15 and Siglec10 have been identified as potential immune checkpoints in cancer, while Siglec2 and Siglec10 play roles in autoimmune diseases like systemic lupus erythematosus (SLE). CONCLUSION: Siglecs are key immunomodulators that mediate cell-cell and pathogen interactions, playing pivotal roles in human diseases. Further research into their mechanisms and clinical applications is essential to fully harness their therapeutic potential. Targeting Siglecs offers promising avenues for developing novel immunotherapies, particularly in cancer and autoimmune diseases.