Siglec-15介导肿瘤免疫逃逸的机制与靶向治疗进展及展望OA

Immune checkpoint blockade targeting the programmed cell death protein-1(PD-1)and its ligand PD-L1 has revolutionized cancer immunotherapy;however,a substantial proportion of patients exhibit primary or acquired resistance,underscoring the existence of PD-1 independent immunosuppressive pathways within the tumor microenvironment.In this context,Sialic acid-binding immunoglobulin-type lectin 15(Siglec-15)has emerged as a distinct immune checkpoint molecule operating independently of the canonical PD-1/PD-L1 axis and has garnered increasing attention in tumor immunology.Siglec-15 is preferentially expressed in multiple solid tumors and tumor-associated myeloid populations,with a spatial expression pattern that is often complementary to that of PD-L1.Functionally,Siglec-15 modulates immune synapse signaling between myeloid cells and effector T lymphocytes,leading to impaired T cell activation,proliferation,and cytokine production,thereby contributing to immune evasion within the tumor microenvironment.Accumulating evidence indicates that Siglec-15 mediated immunosuppression represents a mechanistically distinct pathway that may account,at least in part,for resistance to current immune checkpoint inhibitors.A comprehensive understanding of the structural features of Siglec-15,its regulatory networks,and its context-dependent immunological functions is therefore essential.Elucidating these mechanisms will not only deepen insights into the complexity of tumor immune regulation but also facilitate the rational development of next-generation immunotherapeutic strategies aimed at overcoming resistance to existing checkpoint blockade therapies.