Although CD155 is ubiquitously expressed on the cell surface of both hematopoietic and non-hematopoietic cells, tumor cells significantly upregulate its expression. The interaction of DNAM-1 immunoreceptor on CD8+ T cells and NK cells with CD155 on tumor cells plays an important role in tumor immunity in mice. However, unlike mouse, human CD155 contains two splicing isoforms that encode soluble form of CD155 (sCD155). We showed that the serum level of sCD155 was higher in patients with a variety of cancers than that in healthy individuals, and was correlated with the stage of stomach cancer. These results suggest a hypothesis that sCD155 is involved in the tumor escape. To address this hypothesis, we generated a B16/BL6 tumor transfectant expressing sCD155 (sCD155/BL6) and a control transfectant (mock/BL6). These transfectants were subcutaneously inoculated into mice, the growth was faster in sCD155/BL6 than in mock/BL6. We also found that lung metastasis was remarkably promoted in sCD155/BL6 compared with mock/BL6 after intravenous injection. These results suggest that sCD155 inhibits tumor immune response in primary and metastatic regions. Because DNAM-1 and TIGIT, which is known as an inhibitory receptor, shares the ligand CD155, we next intravenously injected either sCD155/BL6 or mock/BL6 into DNAM-1 KO and TIGIT KO mice for the identification of the ligand for sCD155 in tumor microenvironment. Whereas tumor metastasis of sCD155/BL6 was greater than that of mock/BL6 in TIGIT KO mice, those of sCD155/BL6 and mock/BL6 were comparable in DNAM-1 KO mice. Taken together, these results suggest that sCD155 suppressed DNAM-1-mediated tumor immunity.