Li et al. showed that in macrophages, SHP2 is constitutively neddylated, but in the tumor microenvironment of CRC, the activation of macrophage SIRPα, via tumor cell CD47, results in SHP2 deneddylation by SENP8, which subsequently inhibits the phagocytic activity of tumor-infiltrating macrophages. Here, CD47 is linked to colorectal carcinoma.