The study investigates the role of the nuclear factor ID3 in macrophage activation and its impact on anti-tumor activity. ID3, a lineage-determining factor for Kupffer cells (KC), is shown to control the balance between activating and inhibitory receptors on macrophages, promoting phagocytosis of live tumor cells and recruiting and activating lymphoid effector cells. ID3 shifts the inhibitory/activating receptor balance by buffering the binding of transcription factors ELK1 and E2A at the *SIRPα* locus. Loss- and gain-of-function experiments demonstrate that ID3 is sufficient to endow mouse bone marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages with potent anti-tumor activity. The findings suggest that ID3 could be harnessed for cell therapy in cancer.The study investigates the role of the nuclear factor ID3 in macrophage activation and its impact on anti-tumor activity. ID3, a lineage-determining factor for Kupffer cells (KC), is shown to control the balance between activating and inhibitory receptors on macrophages, promoting phagocytosis of live tumor cells and recruiting and activating lymphoid effector cells. ID3 shifts the inhibitory/activating receptor balance by buffering the binding of transcription factors ELK1 and E2A at the *SIRPα* locus. Loss- and gain-of-function experiments demonstrate that ID3 is sufficient to endow mouse bone marrow-derived macrophages and human induced pluripotent stem-cell-derived macrophages with potent anti-tumor activity. The findings suggest that ID3 could be harnessed for cell therapy in cancer.