Microtubule disruption synergizes with STING signaling to show potent and broad-spectrum antiviral activity

The activation of stimulator of interferon genes (STING) signaling induces the production of type I interferons (IFNs), which play critical roles in protective innate immunity for the host to defend against viral infections. Therefore, achieving sustained or enhanced STING activation could become an antiviral immune strategy with potential broad-spectrum activities. Here, we discovered that various clinically used microtubule-destabilizing agents (MDAs) for the treatment of cancer showed a synergistic effect with the activation of STING signaling in innate immune response. The combination of a STING agonist cGAMP and a microtubule depolymerizer MMAE boosted the activation of STING innate immune response and showed broad-spectrum antiviral activity against multiple families of viruses. Mechanistically, MMAE not only disrupted the microtubule network, but also switched the cGAMP-mediated STING trafficking pattern and changed the distribution of Golgi apparatus and STING puncta. The combination of cGAMP and MMAE promoted the oligomerization of STING and downstream signaling cascades. Importantly, the cGAMP plus MMAE treatment increased STING-mediated production of IFNs and other antiviral cytokines to inhibit viral propagation in vitro and in vivo. This study revealed a novel role of the microtubule destabilizer in antiviral immune responses and provides a previously unexploited strategy based on STING-induced innate antiviral immunity. Activation of innate immune signaling pathways provide potential to induce potent and broad-spectrum antiviral immune response. Meanwhile, modulation of the microtubule network may also disturb the normal replication cycle of viruses to serve as antiviral strategy. It is interesting to define whether the combination of the agonists of innate immunity and MDAs could be used in the treatment of viral infection. In this study, we show that MDAs synergize with cGAMP-mediated STING signaling pathway to show broad-spectrum antiviral activity. We reveal that MMAE, a clinically used MDA in tumor treatment, disrupts microtubule network and alters STING trafficking signaling. The MMAE and cGAMP co-treatment enhances the TBK1-STING-IRF3 cascade, type I IFNs induction, and NF-kB immune response of the STING signaling. Importantly, the combination of MMAE and cGAMP triggers promising antiviral effect in vitro and in vivo in a STING-dependent manner. Thus, these findings could help inform future antiviral drugs by modulating cGAS-STING DNA sensing signaling and microtubule network.