Siglec-9: A pivotal immune checkpoint connecting immune homeostasis with the pathogenesis of multiple diseases

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) functions as a critical hub connecting immune homeostasis and disease pathology. By recognizing "self"-associated sialylated modifications, it plays a complex and central role in maintaining physiological balance and driving disease progression. This review systematically integrates empirical research to comprehensively elucidate the biological basis of Siglec-9 and its mechanisms in various pathological states, including cancer, infection, chronic inflammation, neurodegenerative diseases, and metabolic disorders. Critically, dysregulated Siglec-9 signaling constitutes a shared pathogenic hub across diseases. Within the tumor microenvironment, it mediates immunosuppression and immune escape. During infections, pathogens exploit this pathway through molecular mimicry to evade host defenses, and its expression and genetic variants are significantly associated with susceptibility and severity in chronic diseases. Based on these mechanisms, Siglec-9 has emerged as a highly promising diagnostic biomarker, molecular imaging target, and therapeutic candidate. Intervention strategies, such as blocking antibodies, small-molecule inhibitors, and cell therapies, show significant preclinical promise. This review ultimately establishes the importance of targeting Siglec-9 and the related sialic acid-Siglec axis to develop innovative treatment strategies for various refractory diseases and identifies key directions and challenges for future translational research.