NFE2L2 and neoplasm: We demonstrated that (1) SFN selectively increased VSVΔ51 infectivity and cell death in cancer cells, (2) the combination of SFN and VSVΔ51 decreased tumor volume and increased survival in vivo, (3) VSVΔ51 replication was dependent on activation of the Nrf2 pathway, (4) VSVΔ51 replication relied on Nrf2/HO-1-mediated autophagy, and (5) activation of autophagy through the Nrf2/HO-1 axis suppressed the innate antiviral response by inhibiting IRF3 activity.