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Radiotherapy (RT) can prime the immune system against cancer but often fails to generate effective antitumor responses due to concomitant induction of immunosuppressive factors. To overcome this limitation, we built upon the observation that RT enhances adeno-associated vectors (AAVs) tumor transduction through the epigenetic modification of vector episomes. We designed an AAV-based platform to deliver immunostimulatory cytokines through an interferon (IFN)-inducible promoter that allows for spatial control of transgene expression into irradiated tumors. As opposed to a constitutive system, local delivery of a vector encoding for inducible IL-12 (AAV-iIL12) achieves an efficient production of the cytokine without significant toxicity. Combination of RT and AAV-iIL12 generates a highly immunostimulatory tumor microenvironment (TME) leading to robust local and systemic antitumor responses in an IFNγ- and FAS-dependent manner, able to overcome common immune-evasion mechanisms. Our work shows that radiation coupled with AAV-based immune-gene delivery is an efficient and safe approach to treat cancer.