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Colorectal cancer is the third most common cancer worldwide and shows resistance to immune checkpoint inhibitors which have been demonstrated to be effective in many other types of cancers. Pre-existing T-cell response in tumor microenvironment often determines the therapeutic benefit of immune checkpoint blockade. Tumor-infiltrating CD8+ T-cells are considered as the major effector immune cells in antitumor immunity. In this study, we aimed to identify the intrinsic oncogenic pathway that contributes to a reduction of CD8+ T-cell infiltration in colorectal cancer. To achieve this, human colon adenocarcinoma samples derived from The Cancer Genome Altas (TCGA) were stratified into low T-cell-inflamed and high T-cell-inflamed groups based on the expression of T-cell signature genes. Gene set enrichment analysis of revealed a close correlation between activation of the Wnt/β-catenin signaling pathway and absence of T-cell infiltration. By immunohistochemical analysis of 155 colorectal cancer tissues, we found that tumors with high β-catenin expression showed a significant reduction of CD8+ T-cell infiltration. Mechanistically, β-catenin can regulate CCL4 expression to recruit CD103+ dendritic cells to enable CD8+ T cell activation. Collectively, our data indicate that oncogenic β-catenin signal may mediate colorectal cancer resistance to immunotherapies, pointing to the combined PD-1-immunotherapy with targeting β-catenin in colorectal cancer. more...