A STING agonist-loaded bispecific nanobioconjugate modulates macrophage immune responses to enhance antitumor immunotherapy

Tumor-associated macrophages (TAMs) have become attractive therapeutic targets because of their multifaceted cancer-promoting functions and their abundance in the tumor microenvironment (TME). Here, we construct a stimulator of interferon genes (STING) agonist-loaded bispecific nanobioconjugate for macrophage-mediated cancer immunotherapy. Calcium phosphate (CaP) is used as a carrier to load STING agonist, 2',5'-3',5' cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), to prepare cGAMP-loaded CaP nanoparticles (cGAMP@CaP). Two types of antibodies, anti-CD47 antibody (aCD47) and anti-SIRP alpha antibody (aSIRP alpha), are modified on the CaP nanoparticles (cGAMP@CaP@Abs). The resulting STING agonist-loaded bispecific nanobioconjugate not only enhances macrophage phagocytosis through blocking of the CD47-SIRP alpha axis and the physical bridge of macrophages and tumor cells but also potentiates the activation of the STING pathway by cGAMP in TAMs, accordingly effectively triggering a type I interferon-driven inflammatory program. The nanobioconjugate can target and accumulate at the tumor site, facilitate the infiltration of CD8(+) T cells, and reprogram the immunosuppressive tumor microenvironment, achieving remarkable therapeutic efficacy in multiple murine tumor models. Overall, the STING agonist-loaded bispecific nanobioconjugate provides a novel platform for macrophage-mediated tumor immunotherapy.