We identify CDKN1A (p21) as a transcriptional repressor of the phagocytosis inhibitory receptor SIRPα and consequently as a therapeutic target for overcoming the CD47-dependent phagocytosis resistance mechanism of cancer cells (such as that of T-cell acute lymphoblastic leukemia (T-ALL) cells) and for inducing the proinflammatory activation of macrophages after cancer cell engulfment. The gene discussed is CDKN1A; the disease is cancer.