Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment for their unprecedented clinical efficacy. Signal regulatory protein α (SIRPα) is a phagocytic checkpoint expressed on macrophages, dendritic cells, and other myeloid cells. Cancer cells inhibit macrophage phagocytosis through the interaction of the CD47–SIRPα axis. Disrupting the CD47–SIRPα axis has therefore been a promising strategy in restoring the immune attack against cancer. Herein, we engineered cellular membrane nanovesicles (NVs) presenting SIRPα receptors for phagocytosis checkpoint blockade to augment the antitumor immune response. Furthermore, zebularine (Zeb), an inhibitor of DNA methyltransferase, was encapsulated into SIRPα NVs to reprogram the immunosuppressive tumor microenvironment together with blockade of phagocytosis checkpoint. It is demonstrated that SIRPα@Zeb can improve tumor immunogenicity, the polarization of tumor-associated macrophages to the M1 phenotype, and increase the infiltration of CD8⁺ T lymphocytes in tumors. The robust antitumor immune response induced by SIRPα@Zeb significantly suppressed tumor growth and extended mice-bearing melanoma xenograft survival.