Sorafenib suppresses the activation of type I interferon pathway induced by RLR-MAVS and cGAS-STING signaling.

ABSTRACT

Type I interferon pathway is a crucial component of innate immune signaling upon pathogen infection or endogenous instability. An imbalance of type I interferon can lead to many diseases, such as autoimmune diseases and inflammatory diseases. Meanwhile, the side effects of clinical drugs on type I interferon signaling may result in impaired outcomes in clinical treatment, especially in cancer immunotherapy which is associated with type I interferon signaling. Here, we found that sorafenib, an FDA-approved drug for HCC chemotherapy, suppresses both DNA- and RNA-sensing mediated type I interferon pathway. Mechanistically, sorafenib treatment induces the autophagic degradation of MAVS, cGAS, TBK1, and IRF3, and attenuates the signaling transduction. In addition, sorafenib also inhibits the recruiting of STING or MAVS with TBK1 and IRF3. This work reveals the negative role of sorafenib in the regulation of type I interferon pathway. Sorafenib treatment is not only a potential drug for autoimmune disease and inflammation diseases, but also needs to be noticed in HCC chemotherapy.