Dual targeting of ENPP3 and SIRPα with a bispecific antibody enhances macrophage-mediated immunity in renal cell carcinoma

Renal cell carcinoma (RCC) remains a therapeutic challenge despite recent immunotherapy advances. We identified ENPP3 and SIRPα as significantly overexpressed in RCC tissues with positive correlation and prognostic relevance. Based on these findings, we developed a novel bispecific antibody simultaneously targeting tumor-associated ENPP3 and macrophage checkpoint SIRPα. The ENPP3-SIRPα bispecific antibody demonstrated specific binding to both targets and effectively blocked CD47-SIRPα interaction in vitro. In vivo this bispecific approach exhibited superior anti-tumor efficacy compared to monotherapies or their combination as separate agents. Mechanistic studies confirmed that the therapeutic effect was macrophage-dependent, with enhanced phagocytosis of tumor cells. Importantly, the bispecific antibody maintained a favorable safety profile with no significant hematological abnormalities observed during treatment. These findings demonstrate that simultaneous targeting of ENPP3 and SIRPα represents a promising immunotherapeutic strategy for RCC, combining tumor-specific targeting with immune checkpoint inhibition while mitigating potential toxicities associated with systemic SIRPα blockade.