Neuropilin-1 (NRP1) and Siglec-15 are two emerging and functionally complementary regulators within the tumor immune microenvironment (TIME). These molecules contribute to tumor progression through distinct mechanisms involving tumor-supportive signaling pathways and immune suppression, respectively, providing a strong biological rationale for simultaneous targeting using a bispecific antibody approach.

NRP1 is a transmembrane glycoprotein originally identified as a co-receptor involved in axon guidance and angiogenesis. It is overexpressed in a wide range of solid tumors and functions as a co-receptor for ligands such as VEGF-A and semaphorins, thereby promoting tumor angiogenesis, cell migration, and invasive behavior. Importantly, NRP1 is highly expressed on regulatory T cells within the tumor microenvironment, where it contributes to Treg stability and immunosuppressive activity, facilitating tumor immune escape.

Siglec-15 is a recently identified immune suppressive molecule of the Siglec family, predominantly expressed on tumor-associated macrophages, dendritic cells, and certain tumor cells. Siglec-15 suppresses T-cell activation and effector functions through sialic acid–dependent inhibitory signaling. Notably, Siglec-15 expression is often mutually exclusive or inversely correlated with PD-L1, highlighting its potential as an alternative immune checkpoint target, particularly in patients with limited response to PD-1/PD-L1 blockade.

Mechanistically, NRP1 primarily modulates tumor-supportive and immunosuppressive components of the microenvironment, whereas Siglec-15 directly mediates inhibitory immune signaling. A bispecific antibody targeting both NRP1 and Siglec-15 enables coordinated disruption of these complementary pathways within a single therapeutic modality, potentially enhancing antitumor immune responses and broadening the applicability of cancer immunotherapy.

Based on this strong mechanistic and immunological rationale, the NRP1 × Siglec-15 bispecific antibody program represents a differentiated and promising strategy in cancer immunotherapy. 

References：

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