A variety of trials of immunotherapy in metastatic melanoma have clearly demonstrated that immune responses against melanoma can be induced, but only a few patient have responded clinically, suggesting that new strategies to enhance anti-cancer immune responses are needed. Most of these immunotherapy trials have focused on antigen delivery and providing stimulatory antigen-specific signals to T cells. However, the induction of antigen-specific T cell-mediated immune responses is regulated not only by stimulatory signals, but also by inhibitory receptor-mediated signals. Studies have demonstrated that administering mAbs targeting such immune-modulating receptors on T cells enhances vaccine-induced anti-tumor immunity, suggesting that such an approach might improve the efficacy of clinical cancer vaccines. However, systemic administration such mAbs has been associated with severe, sometimes fatal, autoimmunity. We have developed an approach for targeted delivery of such immune modulatory proteins and mAbs, using immune modulator RNA-transfected dendritic cells (DC), to sites where anti-tumor T cells are induced. Our preliminary studies indicate that this approach may eliminate the adverse effects associated with systemic administration immune modulators, while also enhancing vaccine-induced immune responses.