Synthetic biology is a rapidly evolving multidisciplinary field that combines biology and engineering to develop artificial biological systems with novel functions. This approach has been implemented to generate effective, practical solutions for biomedicine. For example, cancer immunotherapy recently demonstrated remarkable success in clinical trials, but remains limited by the rarity of targetable tumor-specific antigens, tumor-mediated immune suppression and the cytotoxicity caused by systemic immunomodulators administration. We developed a synthetic gene circuit for cancer immunotherapy that could overcome these obstacles. The circuit identifies tumor-specific transcriptional signatures and generates the expression of potent immunomodulators selectively from within the cancer cells. Thus, these cancer cells function as ‘Trojan horses’ that initiate potent anti-tumor immune response. Lentiviral circuit delivery significantly reduced tumor size in vivo and prolonged mouse survival. This approach has the potential to enable powerful new immunotherapies and to study tumor immunology.