Oncolytic viruses (OVs) have made tremendous strides as a viable cancer therapeutic in recent years; however, variable infectivity rates have since limited clinical efficacy. Residual type 1 interferon (IFN-1) responses are integral to the tumour’s innate antiviral defense and confer resistance to OVs. To combat this, small molecules with viral sensitizing ability can be used in combination to transiently knockdown IFN-1 responses, allowing OVs to gain a foothold for increased infectivity and therapeutic efficacy. Accordingly, we hypothesize that some chemical or genetic manipulations of cellular processes can indirectly antagonize antiviral IFN-1 responses and modulate pro-inflammatory pathways to potentiate oncolytic virotherapy. In this thesis, we identify several avenues to modify cell signalling events to increase OV therapeutic efficacy through IFN-1 inhibition. Firstly, with respect to the demonstrated OV-enhancing effects of vanadium, a pan-phosphatase (PP) inhibitor, we elucidate that its IFN-1 suppressing activity involves activation of the epidermal growth factor receptor (EGFR) pathway via STAT1/2 and NF-κB. Pharmacological inhibition of EGFR abrogated vanadium’s viral sensitizing ability in vivo. Secondly, using high-throughput screening methodology, we identify protein phosphatases that inherently regulate the IFN-1 response as targets for oncolytic vesicular stomatitis virus (VSV∆51) potentiation. Indeed, cloning interfering RNA against one of these PP targets, acid phosphatase 2 (ACP2), into the VSV∆51 platform demonstrated superior infectivity and cancer cell cytotoxicity compared to the non-targeting VSV∆51 control. Thirdly, we characterize pevonedistat, a first in-class neddylation activating enzyme inhibitor, to potentiate OV therapeutic efficacy across several in vitro and in vivo contexts. We demonstrate pevonedistat’s ability to inhibit IFN-1 signalling and pro-inflammatory cytokine production using both neddylation independent and dependent mechanisms. Taken altogether, we dissect multiple signaling mechanisms by which the IFN-1 response can be modulated for the purposes of improving OV therapeutic efficacy. This knowledge can subsequently be directly translated into designing optimized OV strategies for clinical testing.