**5. Naturally Oncolytic Viruses Exploit the Altered Cancer-Cell Milieu**

The combined metabolic and defense-defective features of the cancer cell milieu (see schematic depiction in Figure 1) can be exploited in the context of oncolytic virotherapy. This is particularly relevant for viruses that are naturally devoid of human diseasecausing potential but retain the potential to replicate in, and kill, malignant cells. Such viruses are referred to here as "naturally oncolytic" viruses, to differentiate them from "armed/engineered oncolytic viruses". Examples of "naturally oncolytic" viruses include attenuated clones of human pathogens (e.g., vaccine clones of measles and mumps viruses, [161]), viruses of veterinary origin (e.g., Newcastle disease virus (NDV), VSV, rat parvovirus (H-1PV), [162–165]) or the mammalian reovirus, a virus naturally devoid of disease-causing potential [47]. Indeed, we explored the complete absence of IFN signaling in LNCaP prostate cancer cells [120,121], which also present oncogenic KRAS mutation [166], to select an oncolytic mutant of the epizootic hemorrhagic disease virus (EHDV), an orbivirus (arbovirus of the Reoviridae family) that naturally targets ruminants, and that we named EHDV-Tel Aviv University (EHDV-TAU) [120]. Our studies demonstrate productive infection of EHDV-TAU in cells with defective IFN/antiviral responses, e.g. the absence of JAK1 expression/function in LNCaP prostate cancer cells [120,167], or the low basal expression levels of PRRs and defective induction of IFN (following viral infection) by B16F10 murine melanoma cells [152]. Moreover, in the latter case, treatment with inhibitors of epigenetic silencing restored PRR expression and viral induction of IFN responses in the B16F10 cells; exemplifying the role of epigenetic silencing of IFN/ISGs in the cancer cell, as a mechanism for OV selectivity. Additionally, our studies revealed that while productive infection was inhibited upon treatment with IFN, EHDV-TAU retained its cell killing potential of LNCaP cells engineered to express JAK1 (LNCaP-JAK1), when infection was carried out in presence of interleukin-6 (IL-6), an inflammatory cytokine and strong activator of cell autonomous immunity [167]. Thus, with dependence on the cellular setting, OVs may also exploit antiviral responses for induction of cancer cell death.
