**2. Combinations Affecting Viral Propagation in Tumor Cells**

The selectivity of various oncolytic viruses largely depends on defects in the tumor cell's innate ability to fend off viral infections [35]. However, the initial assumption that an impaired interferon (IFN) response is a common feature shared by many tumors [36] may not reflect the clinical reality of solid cancers' heterogeneity [37]. Some tumors, such as pancreas cancer, may even display an upregulated antiviral state leading to primary resistance [38]. A constitutive interferon pathway activation was also described as a main determinant for oncolytic measles virus activity in a human glioblastoma specimen [39]. On the other hand, tumors induced by oncoviruses, such as HPV-associated cervical or head and neck cancers, tend to frequently display strongly impaired antiviral innate responses [40]. However, in light of missing systematic assessments of a large range of tumor types, general conclusions as to what cancer types are more antivirally active and which are not remain to be drawn. Although most viruses have evolved to express proteins that counter antiviral measures [41], engineering of many oncolytic viruses were aimed at abolishing exactly those viral counter measures, generating OVs with a heightened IFN sensitivity [37]. Cornerstones of the antiviral innate immune response are type I (and to a lesser extend type III) interferons [42]. Both IFN types converge in their signaling and induce transcriptional responses through the Janus kinase signal transducers and activators of transcription (JAK/STAT) pathway [43]. Their signaling is associated with downstream expression of interferon stimulated genes (ISGs) which act as antiviral effector proteins countering viral replication. OV replication is impaired when these pathways are still intact in the treated tumor cells [44]. In the following, we will discuss various compound classes involved in inhibiting antiviral signaling pathways and which hold the potential to either enhance replication of OVs or even address OV resistance in cancer cells.
