**4. Mechanisms of Oncolysis**

Reovirus was originally considered to operate predominantly by apoptosis (reviewed in [73]). The apoptotic signalling often displayed by infected cells includes the generation of IFN and activation of NF-κB, either through detection of cytoplasmic dsRNA via PKR, retinoic acid-inducible gene I (RIG-I) or melanoma differentiation-associated protein 5 (MDA5), or following σ1 and µ1 receptor engagement or membrane penetration [53,74–77]. In response to NF-κB and/or IRF3 signalling, inflammatory cytokines such as TNF-related apoptosis-inducing ligand (TRAIL) are secreted, which bind to surface death receptors and trigger activation of caspase-3 and -7 [78–80]. While IFN is a potent promoter of cell death, it can be dispensable for reovirus-induced apoptosis, which explains the ability of infected, IFN-deficient tumour cells to undergo apoptosis [79,81]. Blockade of apoptotic caspases does not always abrogate reovirus-induced cell death, indicating that other modes of cell death can also occur [82]. Necroptosis, contingent on recognition of viral dsRNA and induction of a type I IFN response [83], and autophagy following acute endoplasmic reticulum (ER) stress [84] have both been identified as alternative modes of reovirus-induced cell death. Thus, reovirus-induced death is exquisitely linked to the phenotype of the target cell and the surrounding TME; indeed, our recent unpublished data suggest that modulation of pro- vs. anti-apoptotic proteins upon co-culture with stromal cell support can abrogate reovirus-induced apoptosis in malignant B cells. Therefore, examination of viral replication and/or oncolysis in multiple cancer models, and in the context of TME support, will be essential to identify mechanisms of cancer-selective activity and cell death.
