*4.7. Stimulator of Interferon Genes (STING)*

The cyclic guanosine monophosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS)-stimulator of the interferon genes (STING) signaling pathway has recently been described as playing an important role, not only in the innate response to infection [275–278], but also in cancer immune surveillance. STING activation initiates a type I interferon (IFN)-driven pro-inflammatory program that stimulates basic leucine zipper transcriptional factor ATF-like 3 (BATF3)-dependent dendritic cell (DC) cross-presentation and promotes CD8<sup>+</sup> T cell-mediated anti-tumor immune responses [279–282]. STING agonists have thus emerged as a class of promising new therapeutics that may enhance tumor immunogenicity and several candidates are being evaluated in pre-clinical and clinical contexts [283–285]. However, STING deficiency is common in several cancer entities due to the anti-tumorigenic and immune-activating role of STING signaling [286–288] and data suggest that, consequently, oncolytic viruses benefit from STING loss due to a decreased antiviral IFN response [287,288]. Several OVs also encode gene products that interfere with the cGAS–STING signaling pathway [289,290]. These considerations make a potential combination of OV with STING agonists at first look counterintuitive. However, STING deficiency or dysfunction has been associated with an exclusion of lymphoid cells from the TME [279] and, while viral replication may be enhanced in STING loss tumors, an optimal induction of an adaptive anti-tumor immune response could be hindered. Indeed, OVs that induce an IFN response via cGAS-STING signaling may have an advantage due to the involvement of this pathway in the bridging of innate and adaptive immunity [291]. Hence, the combination of small molecule STING agonists with certain oncolytic viruses may represent an interesting novel approach to enhance anti-tumor immune responses in OV therapy, although careful assessment of the co-treatment regimen to balance the antiviral and antitumoral effects of STING will be paramount.
