Mechanisms of tumor immune escape mediated by Siglec-15 and advances and prospects in targeted therapy

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.