Localized Delivery of the mRNAs Encoding CD47 Inhibitor and Interleukins 12, 15, and 21 Elicits Robust Antitumor Immunity

Abstract 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.