Snail is primarily known as a transcriptional repressor that induces epithelial-mesenchymal transition by suppressing adherent proteins. Emerging evidence suggests that Snail can act as an activator; however, the mechanism and biological significance are unclear. Here, we found that CREB-binding protein (CBP) is the critical factor in Snail-mediated target gene transactivation. CBP interacts with Snail and acetylates Snail at lysine 146 and lysine 187, which prevents the repressor complex formation. We further identified several Snail-activated targets, including TNF-α, which is also the upstream signal for Snail acetylation, and CCL2 and CCL5, which promote the recruitment of tumor-associated macrophages. Here, we present our results on the mechanism by which Snail induces target gene transactivation to remodel the tumor microenvironment. Display omitted •TNF-α potentiates CBP-induced acetylation of Snail at lysine 146 and lysine 187•Acetylation of Snail prevents the formation of the Snail repressor complex•Acetylation of Snail induces transcription of TNFA, CCL2, and CCL5•Acetylation of Snail promotes the recruitment of tumor-associated macrophages Hsu et al. report that Snail acetylation by CBP prevents repressor complex formation and allows target gene transactivation. Snail-mediated transactivation of TNFA provides the upstream signal for Snail acetylation, whereas that of CCL2 and CCL5 promotes tumor-associated macrophage recruitment.