Targeting CD37 promotes macrophage-dependent phagocytosis of multi cancer cell types and facilitates tumor clearance in preclinical mouse models

Macrophages play a crucial role in innate and adaptive immunity, and their function is mediated through phagocytosis and antigen presentation. Despite efforts to identify phagocytic checkpoints and explore their mechanisms of action, current checkpoint scanning strategies are unable to provide a complete and systematic list of such immune checkpoints. Here, we use primary healthy donor macrophages co cultured with breast cancer cells for in vitro phagocytosis assay, and then carry out ribosome analysis on the sorted macrophages to identify immune system specific checkpoints. Interestingly, we observed downregulation of CD37 in phagocytic macrophages and demonstrated that targeting CD37 with specific antibodies can promote phagocytosis of various cancer cells in vitro. Mechanistically, tumor derived macrophage migration inhibitory factor (MIF) directly binds to CD37, activating the transduction cascade involving recruitment of SHP1 and inhibition of AKT signaling, ultimately impairing phagocytosis. In vivo, targeting CD37 can promote tumor clearance in various preclinical mouse models and synergize with anti-CD47 therapy. Therefore, our study identified a previously unidentified phagocytic checkpoint and provided new potential for precise treatment.