Cancer vaccines based on mRNAs that encode tumor associated antigens are considered as a promising approach to treat cancer. However, like dendritic cell based vaccines, mRNA cancer vaccines seldom resulted in a complete cure of the enrolled patients. The immunosuppressive tumor environment, which prevents immune cells to attack tumor cells, is an important reason for the limited success of cancer vaccines. Therefore, therapeutic cancer vaccines should be combined with strategies that tackle the immunosuppressive tumor environment. Additionally, a specific antitumor response after cancer vaccination takes time to develop. Consequently, a sore point of therapeutic cancer vaccines is that they lack an acute effect, which renders them ineffective in controlling a rapidly growing tumor on their own. IL-12 is an interesting cytokine with an rapid antitumor effect. Therefore, in this project we purpose a combinatorial immunotherapy that makes use of a new generation of RNA therapeutics, the so-called synthetic amplified RNA (SafeR) vectors, that have been designed in collaboration with MIT. Our combinatorial cancer immunotherapy consist out of: (1) a SafeR vaccine encoding MAGE-B, (2) a SafeR vector that produces IL-12 under control of a FDA approved drug, and (3) an indoleamine 2,3-dioxygenase-1 inhibitor to reduce the immunosuppressive tumor environment. We will evaluate this combinatorial cancer immunotherapy and its different arms in our novel metastatic breast cancer model.