Carcinogenesis is the process by which normal cells become malignant. It typically occurs through the accumulation of mutations that dysregulate intracellular signaling pathways and lead to unchecked growth and proliferation. Oncolytic viruses (OV) are replication conditional virus mutants that take advantage of these overactivated growth pathways to selectively replicate in and lyse tumor cells. In addition to the direct infection and lysis of tumor cells, OVs also kill tumor cells through disruption of tumor vasculature and the induction of potent anti-tumor immune responses. Clinical efficacy of OVs remains relatively poor, attributed to therapeutic barriers such as poor tumor penetration, premature viral clearance, and the presence of highly resistant cancer stem cell (CSC) subpopulations. Efforts to enhance OV efficacy include the addition of transgenes to enhance anti-tumor immunity, as well as combination therapy with cytotoxic and/or immunosuppressive drugs to increase tumor cell death and reduce innate antiviral responses. The growth compromised HSV-2 mutant ΔPK, has robust oncolytic activity in both melanoma cultures and xenografts associated with the induction of multiple pathways of programmed cell death. However, the impact of ΔPK on putative CSC populations, as well as its ability to harness immune responses that contribute to tumor cell death is still poorly understood. This thesis work sought to answer these questions as well as investigate the potential benefits of combining ΔPK with valproic acid (VPA), a histone deacetylase inhibitor with demonstrated cytotoxic and immunosuppressive properties. We report that: (i) ΔPK prevents anchorage-independent growth and lyses 3D cultures through calpain-dependent clearance of the autophagy protein p62/SQSTM1, (ii) ΔPK oncolysis includes several features of immunogenic cell death, such as the inhibition of Th2-based immunosuppressive conditions, promotion of a Th1-biased microenvironment, and the induction of anti-tumor immune surveillance mechanisms, (iii) VPA induces a novel calpain-dependent necroptotic form of cell death in neuronal cells, and (iv) the combination of VPA and ΔPK treatment in melanoma increases ΔPK -induced cell death through enhanced caspase activation. These findings suggest that ΔPK is a multi-mechanistic OV with particularly promising cancer therapeutic potential, and warrant further in vivo investigation into the oncolytic potential of the ΔPK and VPA combination.