A one-two, CAR-T cell punch Chimeric antigen receptor (CAR)–T cells have been clinically effective in killing certain hematological malignancies, but achieving long-term patient responses for solid tumors remains a challenge. Reinhard et al. describe a two-part “CARVac” strategy to overcome poor CAR-T cell stimulation and responses in vivo. They introduce the tight junction protein claudin 6 (CLDN6) as a new CAR-T cell target and designed a nanoparticulate RNA vaccine encoding a chimeric receptor directed toward CLDN6. This lipoplex RNA vaccine promotes CLDN6 expression on the surface of dendritic cells, which in turn stimulates and enhances the efficacy of CLDN6-CAR-T cells for improved tumor therapy. Science , this issue p. 446