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

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.