**1. Introduction**

The present review focuses on the differential and enhanced susceptibility of cancer cells to oncolytic viruses (OVs). We propose that such hyper-susceptibility of the malignant cells stems from unique features of the cancer-cell milieu, including defective antiviral responses and metabolic reprograming. The sources of such tumor-cell specific alterations

**Citation:** Ehrlich, M.; Bacharach, E. Oncolytic Virotherapy: The Cancer Cell Side. *Cancers* **2021**, *13*, 939. https://doi.org/10.3390/ cancers13050939

Academic Editor: G. Eric Blair

Received: 19 January 2021 Accepted: 12 February 2021 Published: 24 February 2021

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comprise a combination of factors, which are intrinsic to the tumor cell—e.g., oncogenestimulated signaling, and/or extrinsic ones; e.g., selective pressure applied by the tumor immune microenvironment. We begin by focusing on the cancer-cell *per se*, analyzing how oncogene-induced modifications serve to optimize the intracellular environment towards OV replication. To this end, we employ RAS-activated pathways as a pivot, exemplifying how this intrinsic oncogenic pathway modulates antiviral responses. We then proceed to focus on the immunoediting of tumors, as this provides a critical extrinsic (selective) source of alterations to cancer-cell autonomous immune functions. Given the overlap in the immune-activation-potential of a cancer cell and its ability to raise antiviral responses, the selective pressure applied by anti-tumor immunity results in both decreased immunogenicity and in defective antiviral responses. We finalize our review by focusing on oncogene-stimulated DNA methylation in the context of immune evasion, as an example of how the two processes (oncogenic signaling and immunoediting) converge to influence OVs-cancer-cell interactions. Our focus on DNA methylation stems from its prominence as a molecular mechanism for silencing of cell-autonomous immune responses. In this context, we also discuss the reversal of this form of epigenetic silencing, which may elicit tumor immunogenicity through the expression of endogenous retroelements, thus generating a "viral mimicry" state, emulating the immune-stimulatory potential of OVs.
