Hyperactivation of the YAP/TEAD transcriptional complex in cancers facilitates the development of an immunosuppressive tumor microenvironment. Herein, we observed that the transcription factor SP1 physically interacts with and stabilizes the YAP/TEAD complex at regulatory genomic loci in colorectal cancer (CRC). In response to serum stimulation, PKCζ (protein kinase C ζ) was found to phosphorylate SP1 and enhance its interaction with TEAD4. As a result, SP1 enhanced the transcriptional activity of YAP/TEAD and coregulated the expression of a group of YAP/TEAD target genes. The immune checkpoint V-domain Ig suppressor of T-cell activation (VISTA) was identified as a direct target of the SP1-YAP/TEAD4 complex and found to be widely expressed in CRC cells. Importantly, YAP-induced VISTA upregulation in human CRC cells was found to strongly suppress the antitumor function of CD8