Cancer is a major scientific and economical challenge that our society has to face and new therapeutic approaches should now be evaluated in order to decrease human and financial cost of this disease. After suffering from many drawbacks, cancer immunotherapy, which aims at mobilizing the immune system to fight cancer, has recently gained enthusiasm with the completion of several randomized phase III clinical trials. Because of their ability to trigger the innate immune responses, ligands for pattern-recognition receptors (PRRs) have been included in several vaccination protocols. These approaches, however, have unveiled new hurdles. Here we propose to investigate a new approach for cancer immunotherapy in Human, based on the use of PRR ligand-containing tumor cells. We have recently shown that introducing the bacterial protein flagellin into tumor cells stimulates innate immune cells and induces a tumor-specific adaptive immunity. Flagellin recognition by myeloid cells engages three distinct PRRs, but subsequent molecular mechanisms controlling presentation of tumor-associated antigens to T lymphocytes are still poorly defined. In addition, the precise nature of adaptive immune responses that efficiently eradicate tumor cells still needs to be precisely characterized before developing pre-clinical trials in Humans. In this context, flagellin-expressing tumor cells represent a powerful tool to uncover fundamental questions on the control of the adaptive immunity by the innate immune system, which will be necessary for the development of new anti-tumor immunotherapies.