CD47 inhibitors have emerged as promising candidates in cancer immunotherapy by activating macrophage phagocytosis through CD47/SIRPα signal blockade and enhancing dendritic cell antigen presentation. However, their clinical efficacy remains limited and is accompanied by severe side effects, including anemia and hemagglutination. To address these limitations, a localized delivery strategy is developed using lipid nanoparticles to encapsulate mRNA encoding a secreted CD47 inhibitor. This mRNA-derived CD47 inhibitor effectively activated macrophages against cancer cells in vitro. To improve its modest tumor-suppressive effects in vivo, a combination therapy is formulated by co-delivering mRNAs encoding the CD47 ... More
CD47 inhibitors have emerged as promising candidates in cancer immunotherapy by activating macrophage phagocytosis through CD47/SIRPα signal blockade and enhancing dendritic cell antigen presentation. However, their clinical efficacy remains limited and is accompanied by severe side effects, including anemia and hemagglutination. To address these limitations, a localized delivery strategy is developed using lipid nanoparticles to encapsulate mRNA encoding a secreted CD47 inhibitor. This mRNA-derived CD47 inhibitor effectively activated macrophages against cancer cells in vitro. To improve its modest tumor-suppressive effects in vivo, a combination therapy is formulated by co-delivering mRNAs encoding the CD47 inhibitor and a cytokine cocktail (interleukins 12, 15, and 21), achieving synergistic antitumor effects. Notably, this strategy induces robust systemic antitumor immunity and long-lasting immunological memory, effectively suppressing metastatic tumor progression following localized treatment of the primary tumor. Mechanistically, the mRNA-derived CD47 inhibitor promoted the differentiation of conventional type 1 dendritic cells, facilitating T cell cross-priming and activating cytotoxic T cells. Additionally, the cytokine cocktail further augmented the antitumor activity of these cytotoxic T cells. These findings present a promising strategy for advancing clinical cancer treatment, addressing key challenges associated with current CD47 inhibitor therapies.
