Simple SummaryMacrophages are the “big eaters” of the immune system who are in charge of engulfing undesirable substances. Macrophages are vital for the human body as they are instrumental in developing organisms, regulating immune responses, and maintaining a relatively stable internal environment. When the phagocytic capacity of macrophages is impaired, the body is prone to disease. In the context of tumors, tumor cells have their ways to escape from macrophage-mediated phagocytosis. They masquerade as healthy cells by expressing “don’t eat me” signals to fool macrophages and turn the initially anti-tumoral macrophages against the human body, which results in reduced macrophage-mediated phagocytosis. Hence, promoting the phagocytosis of macrophages is an important approach to improving the efficacy of anti-tumor treatment. In this review, we introduced the underlying mechanisms of macrophage-mediated phagocytosis and reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism.AbstractMacrophages are essential for the human body in both physiological and pathological conditions, engulfing undesirable substances and participating in several processes, such as organism growth, immune regulation, and maintenance of homeostasis. Macrophages play an important role in anti-bacterial and anti-tumoral responses. Aberrance in the phagocytosis of macrophages may lead to the development of several diseases, including tumors. Tumor cells can evade the phagocytosis of macrophages, and “educate” macrophages to become pro-tumoral, resulting in the reduced phagocytosis of macrophages. Hence, harnessing the phagocytosis of macrophages is an important approach to bolster the efficacy of anti-tumor treatment. In this review, we elucidated the underlying phagocytosis mechanisms, such as the equilibrium among phagocytic signals, receptors and their respective signaling pathways, macrophage activation, as well as mitochondrial fission. We also reviewed the recent progress in the area of application strategies on the basis of the phagocytosis mechanism, including strategies targeting the phagocytic signals, antibody-dependent cellular phagocytosis (ADCP), and macrophage activators. We also covered recent studies of Chimeric Antigen Receptor Macrophage (CAR-M)-based anti-tumor therapy. Furthermore, we summarized the shortcomings and future applications of each strategy and look into their prospects with the hope of providing future research directions for developing the application of macrophage phagocytosis-promoting therapy.