The p21-initiated, SIRPα-repressed, phagocytosis-guided, IFNγ-dependent proinflammatory macrophage activation of TAMs strongly reduced the leukemic burden and prolonged mouse survival, thus revealing a non-cell-autonomous mechanism to direct the killing of CD47-expressing leukemia cells and harness antitumor innate immunity in a way that could be targeted for cellular therapy against leukemia. This evidence concerns the gene SIRPA and leukemia.