In summary, we provide the first evidence that CDC73 is a key substrate of UBR5 and demonstrate that CDC73 strongly antagonizes UBR5’s profound tumorigenic and metastatic activities via mechanisms of controlling CD8+ T cell-mediated anti-tumor response and increasing tumor cell apoptosis in TME, as well as via cell-intrinsic regulation of β-catenin and E-cadherin in tumor cells. This evidence concerns the gene CD8A and neoplasm.