The Potential of Siglecs and Sialic Acids as Biomarkers and Therapeutic Targets in Tumor Immunotherapy

Simple Summary Sialic acid dysregulation is closely associated with the occurrence and development of tumors. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are a class of receptors that recognize sialic acid and are widely expressed on the surface of various immune cells. In addition to exhibiting immune checkpoint inhibitory functions, Siglecs have a critical role in immune self-recognition and non-self-recognition. Some immune checkpoint inhibitors targeting specific Siglecs have entered clinical trials. However, the efficacy and potential side effects of Siglecs have not been comprehensively analyzed. Previous studies have reported the role of Siglecs in tumors, but the underlying mechanisms have not been elucidated. The elucidation of mechanisms through which Siglecs promote tumor immune escape will enable the development of novel therapeutic strategies. This review aims to describe the complex interactions between Siglecs and their sialic acid ligands in the tumor immune environment and outline the Siglec-associated pathways for developing immunotherapeutic interventions.Abstract The dysregulation of sialic acid is closely associated with oncogenesis and tumor progression. Most tumor cells exhibit sialic acid upregulation. Sialic acid-binding immunoglobulin-like lectins (Siglecs) are receptors that recognize sialic acid and are expressed in various immune cells. The activity of Siglecs in the tumor microenvironment promotes immune escape, mirroring the mechanisms of the well-characterized PD-1/PD-L1 pathway in cancer. Cancer cells utilize sialic acid-linked glycans to evade immune surveillance. As Siglecs exhibit similar mechanisms as the established immune checkpoint inhibitors (ICIs), they are potential therapeutic targets for different forms of cancer, especially ICI-resistant malignancies. Additionally, the upregulation of sialic acid serves as a potential tumor biomarker. This review examines the feasibility of using sialic acid and Siglecs for early malignant tumor detection and discusses the potential of targeting Siglec-sialic acid interaction as a novel cancer therapeutic strategy.