In this study we found that localized delivery of a type I Interferon (IFNβ) to a severe mouse melanoma model (B16F10) by injecting an adeno-associated-virus (AAV) as delivery system directly into the tumor we sensitize animals to respond favorably to anti-PDL1 immunotherapy. Localized AAV-IFNβ delivery results in enrichment of immune cells in the tumor microenvironment. This may supplement immune recognition of tumors by IFNg, which we show to act synergistically with IFNb. Interestingly, we show that the transcription factor Interferon-Regulatory-Factor 1 (IRF1) mimics the activation by IFNg, and IFNb. This even in the absence of a functional interferon system. These novel findings open the possibility for a new melanoma treatment regime, which combines the activities of IFNg, IFNb and IRF1 for as a more potent melanoma treatment.