Immune checkpoint blockade (ICB) and other immunotherapies have revolutionized cancer treatment, but the non-responsiveness of most cancers to ICB-based monotherapy remains a significant problem. A major reason for the non-responsiveness of these so-called ‘cold’ tumors is that they lack an immunogenic tumor microenvironment (TME) and thus escape T-cell killing despite expressing ICB targets. How to selectively intensify the immunogenicity of the TME has been an unmet challenge. Here we propose a new approach that utilizes a new oncolytic mutant of Herpes simplex Virus (HSV)1 to increase the immunogenicity of the melanoma TME by triggering ZBP1-dependent necroptosis in the tumor mass. This new approach derives from our prior work on HSV1, which showed that this virus encodes a suppressor of necroptosis: the RIP homology interaction motif (RHIM) within the viral protein ICP6. Mutating this RHIM generates a virus (HSV1mutRHIM) which can no longer block necroptosis, allowing for the first-time exploitation of HSV1-induced necroptosis for therapeutic purposes. HSV1mutRHIM activates ZBP1-dependent necroptosis from the nucleus both human and mouse cells, and such so-called ‘nuclear necroptosis’ is even more immunogenic than conventional (i.e., cytoplasm-initiated) necroptosis, because it results in the release of nuclear DAMPs, such as HMGB-1, IL-33 and Il-1a, into the extracellular space. These findings allow us to propose the hypotheses that by inducing Z-RNAs formation and directly activating ZBP1 to trigger nuclear necroptosis in cells of the TME, this modified oncolytic HSV1mutRHIM will greatly improve ICB treatment outcomes. In this proposal, we will examine whether induction of nuclear necroptosis by modified oncolytic HSV1 enhance immune infiltrate in the TME (Aim 1) and potentiate ICB-based cancer immunotherapy in mouse models of localized and metastatic melanoma (Aim 2). The successful completion of these Aims will outline a next-generation oncolytic HSV1-based strategy to activate highly inflammatory form necroptosis and potentiate ICB-based cancer immunotherapies, with important clinical ramifications for the treatment of melanoma and other cancers.