Signal Transducer Nanoparticles Enable Siglec‐10/G Blockade Immunotherapy for Breast Cancer Treatment

Abstract Current treatments for breast cancer (BC), particularly triple‐negative BC, are limited in efficacy due to drug resistance and high recurrence rates. CD24, which is highly expressed in BCs and engages with its receptor Siglec‐10/G (Siglec‐10 in humans and Siglec‐G in mice) on immune cells, represents a promising immune checkpoint blockade (ICB) target. As the engagement is mediated by a short signal transducer (ST) peptide displayed on the BC cell surface, targeting the peptide using antibodies has shown to be effective for BC treatment. Herein, an antibody‐free approach is reported to achieve blockade of the CD24‐Siglec‐10/G signaling through the synthesis of signal transducer peptide‐anchored nanoparticles (STNPs). The STNPs can effectively engage with macrophages, promoting enhanced phagocytosis of BC cells, triggering a broad immune response, and ultimately inhibiting tumor growth. The therapeutic effects can be further improved through encapsulation of RRx‐001, a small molecule inhibitor of the CD47‐SIRPα signaling. Compared to the antibody approach, the synthetic nanoparticle approach offers greater efficacy with lower side effects and enables combination therapy through a simple formulation. Moreover, the approach is versatile and could be adapted for targeting other ICB signaling, advancing the next generation of cancer immunotherapy.