Synergistic reprogramming of the tumor immune microenvironment by Senecavirus A and STING agonist

Stimulator of interferon genes (STING) agonists have shown promise in cancer immunotherapy by enhancing type I interferon (IFN-I) signaling. However, the antiviral effects of IFN-I can suppress viral replication, limiting their combination with oncolytic viruses. This study demonstrates that combining a naturally isolated Senecavirus A (SVA) strain with the STING agonist MSA-2 supports synergistic IFN-I activation across multiple tumor models. The combination induces robust innate and adaptive antitumor immune responses without impairing SVA replication. Transcriptomics, immunoblotting and early IRF7 nuclear translocation in B16‑F10 cells are consistent with engagement of the RIG‑I/MDA5-TBK1-IRF7 axis. In vivo, co‑treatment enhanced IFN‑β induction, increased CD8⁺ T‑cell infiltration and reduced tumor burden relative to monotherapies, whereas efficacy was not observed in athymic nude mice, supporting T‑cell dependence. Together, these data provide preclinical evidence that a rational oncolytic virus and STING combination can amplify antitumor immunity without overtly compromising viral persistence.