Determining which tumor neoantigens to target with cancer vaccines is challenging and has been limited to mutation-derived, mostly nonclonal, antigens expressed in the patients' tumors. Garrido and Schrand et al. develop a vaccination method that induces expression of clonal neoantigens via targeted delivery of an siRNA that downregulates the TAP (transporter associated with antigen processing) protein in either DCs or tumor cells in mice. TAP-low DCs can prime polyclonal CD8⁺ T-cell responses against neoantigens induced in TAP-low tumor cells. Targeting the induced antigens is more efficacious than vaccination against mutation-derived tumor antigens and protects mice from TAP siRNA-treated concurrent or relapsing tumors without toxicity. The data highlight how this method could have broad applicability as a vaccine strategy for cancer patients. Read more in this issue on page 856. Original image from Supplementary Fig. S5B. Artwork by Lewis Long.