Nanoparticle‐Enabled Dual Modulation of Phagocytic Signals to Improve Macrophage‐Mediated Cancer Immunotherapy

Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti‐phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro‐phagocytic nanoparticle (SNPACALR&aCD47) that concurrently carries CD47 antibody (aCD47) and a pro‐phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell‐surface CD47 and block the CD47‐SIRPα pathway to inhibit the “don't eat me” signal. Tumor cell‐targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an “eat me” signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti‐tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti‐phagocytic signals and activation of pro‐phagocytic signals can be effective in macrophage‐mediated cancer immunotherapy. The phagocytosis of tumor cells by macrophages requires both the coordinated disruption of “don't eat me” signals and simultaneous activation of “eat me” signals. Herein, a nanoparticle‐enabled strategy is proposed to concurrently modulate the cell surface levels of calreticulin (CALR) and CD47 to improve macrophage phagocytosis for improved cancer immunotherapy.