Macrophages eliminate abnormal cells through phagocytosis, yet their phagocytic ability toward tumor cells is hindered by elevated "don't eat me" signals (e.g., CD47) and insufficient pro-phagocytic signals (e.g., calreticulin, CRT) within the tumor microenvironment. Efficient modulation of macrophage phagocytosis remains a key challenge for immunotherapies. Here, we propose an "AND" logic-gated strategy based on biomimetic nanoparticles to enhance macrophage phagocytosis for improved cancer immunotherapy. The hybrid cell-membrane nanovesicles (Fus-CMVs) were constructed by fusing plasma membranes from engineered 293T cells expressing a high-affinity SIRPα variant to block CD47 (Signal A) with membranes from doxorubicin-pretreated 4T1 tumor cells to display CRT (Signal B). In vitro and in vivo studies demonstrated that the "AND" logic-gated Fus-CMVs significantly increased macrophage engulfment of tumor cells and remarkably inhibited tumor growth in different tumor models when compared with single-signal controls. This approach offers a promising approach to enhance macrophage-mediated antitumor immunotherapy.
Zhang et al. (Thu,) studied this question.