PD-L1 expression is elevated in various human cancers, including colorectal cancer. High levels of PD-L1 expressed on tumor epithelial cells are one of the potential mechanisms by which tumor cells become resistant to immune attack. However, PD-L1 regulation in tumor cells is not fully understood. Here we demonstrate that mutations in the adenomatous polyposis coli (APC) gene lead to colonic epithelial cell resistance to CD8 T cell cytotoxicity by induction of PD-L1 expression. Mechanistically, this occurs as a result of the β-catenin/TCF4 complex binding to the PD-L1 promoter, leading to increased transcription. Our findings not only reveal a novel mechanism by which APC mutations induce tumor immune evasion via an immune checkpoint pathway but also pave the way for developing β-catenin or TCF4 inhibitors as possible new options for immune checkpoint inhibition.