*Review* **Oncolytic Virotherapy: The Cancer Cell Side**

**Marcelo Ehrlich \* and Eran Bacharach \***

Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 6997801, Israel

**\*** Correspondence: marceloe@tauex.tau.ac.il (M.E.); eranba@tauex.tau.ac.il (E.B.)

**Simple Summary:** Oncolytic viruses (OVs) are a promising immunotherapy that specifically target and kill cancer cells and stimulate anti-tumor immunity. While different OVs are endowed with distinct features, which enhance their specificity towards tumor cells; attributes of the cancer cell also critically contribute to this specificity. Such features comprise defects in innate immunity, including antiviral responses, and the metabolic reprogramming of the malignant cell. The tumorigenic features which support OV replication can be intrinsic to the transformation process (e.g., a direct consequence of the activity of a given oncogene), or acquired in the course of tumor immunoediting—the selection process applied by antitumor immunity. Oncogene-induced epigenetic silencing plays an important role in negative regulation of immunostimulatory antiviral responses in the cancer cells. Reversal of such silencing may also provide a strong immunostimulant in the form of viral mimicry by activation of endogenous retroelements. Here we review features of the cancer cell that support viral replication, tumor immunoediting and the connection between oncogenic signaling, DNA methylation and viral oncolysis. As such, this review concentrates on the malignant cell, while detailed description of different OVs can be found in the accompanied reviews of this issue.

**Abstract:** Cell autonomous immunity genes mediate the multiple stages of anti-viral defenses, including recognition of invading pathogens, inhibition of viral replication, reprogramming of cellular metabolism, programmed-cell-death, paracrine induction of antiviral state, and activation of immunostimulatory inflammation. In tumor development and/or immunotherapy settings, selective pressure applied by the immune system results in tumor immunoediting, a reduction in the immunostimulatory potential of the cancer cell. This editing process comprises the reduced expression and/or function of cell autonomous immunity genes, allowing for immune-evasion of the tumor while concomitantly attenuating anti-viral defenses. Combined with the oncogene-enhanced anabolic nature of cancer-cell metabolism, this attenuation of antiviral defenses contributes to viral replication and to the selectivity of oncolytic viruses (OVs) towards malignant cells. Here, we review the manners by which oncogene-mediated transformation and tumor immunoediting combine to alter the intracellular milieu of tumor cells, for the benefit of OV replication. We also explore the functional connection between oncogenic signaling and epigenetic silencing, and the way by which restriction of such silencing results in immune activation. Together, the picture that emerges is one in which OVs and epigenetic modifiers are part of a growing therapeutic toolbox that employs activation of anti-tumor immunity for cancer therapy.

**Keywords:** oncolytic viruses; immunoediting; oncogenic signaling; RAS; DNA methyltransferase inhibitor (DNMTi); viral mimicry; epigenetic silencing
