The poliovirus receptor CD155 and its family member CD112 (nectin-2) are the ligands for the activating cell-surface receptor DNAM-1 on CD8⁺ T cells and natural killer (NK) cells. Here, we demonstrate that, whereas the RMA tumor grew in syngeneic mice, DNAM-1 ligand-transduced RMA was rejected, in which CD8⁺ T cells and NK cells played an essential role. Importantly, CD8⁺ memory cytotoxic T cells to parental RMA were generated in these mice. We found that DNAM-1 was also expressed on CD8α⁺, rather than CD8α^-, dendritic cells (DCs). Cross-linking DNAM-1 induced maturation of CD8α⁺ DCs. Antigen presentation by these stimulated DCs drove Th1 cells. Moreover, the rejection of DNAM-1 ligand-transduced RMA was canceled in CD4⁺ T-cell–depleted and major histocompatibility complex class II–deficient mice. Taken together, these results suggest that DNAM-1 ligands stimulate innate immunity by CD8α⁺ DCs as well as NK cells, which efficiently prime cell-mediated tumor-specific immunity.