We identified here mechanism by which hAEC exert their anti-cancer effects. We showed that vaccination with live hAEC conferred effective protection against murine colon cancer and melanoma but not against breast cancer in orthotopic cancer cell inoculation model. hAEC induced strong cross-reactive antibody response to CT26 cells, but not against B16F10 and 4T1 cells. Neither heterotopic injection of tumor cells in AEC-vaccinated mice nor vaccination with hAEC lysate conferred protection against melanoma or colon cancer. Nanosized AEC-derived exosomes (ADE) induced apoptosis in CT26 cells and inhibited their proliferation. Co-administration of ADE with tumor cells substantially inhibited tumor development and increased CTL responses in vaccinated mice. Our results clearly showed that it is ADE but not the cross-reactive immune responses against tumor cells that mediate inhibitory effects of hAEC on cancer development. Our results highlighted the potential anti-cancer effects of exosomes derived from hAEC.