BACKGROUND: SKV-012 is a novel engineered oncolytic virus (containing the viral neurovirulence ICP34.5 gene transcribed by the Survivin promoter with an upstream genetic component of interleukin-12 (IL-12) driven by the cytomegalovirus promoter) that preferentially replicates in tumors and helps stimulate antitumor immune responses. METHODS: We evaluated SKV-012's safety and efficacy in preclinical models. In a phase I trial, patients with advanced solid tumors received intratumoral injections of escalating doses of SKV-012. Primary endpoints were safety and tolerability, while secondary endpoints were antitumor response and changes in the tumor microenvironment (TME), assessed by RECIST v1.1 criteria and multiplex immunohistochemistry and single-cell transcriptome analysis. RESULTS: SKV-012-infected tumor cells secreted high levels of IL-12 and exhibited increased ICP34.5 expression. The combination of oncolytic herpesvirus and IL-12 was proven to reshape the TME by increasing the infiltration of immune cells, thereby significantly inducing immune cell-mediated cytolysis of tumor cells both in vitro and in animal models. Based on this, we then tested the safety, efficacy and immunogenicity of SKV-012 in patients with advanced solid cancers in a phase I clinical trial (NCT06080984). No dose-limiting toxicities were observed, and adverse events were mild. Three patients achieved partial responses; one had stable disease and two had progressive disease. SKV-012 altered the TME, increasing CD8+ T cells, conventional dendritic cells, and programmed death-ligand 1 expression. CONCLUSIONS: Intratumoral SKV-012 injections demonstrated a favorable safety profile and promising efficacy in animal models and patients with advanced cancers, thereby implicating its potential for clinical application in treatment-resistant advanced solid tumors.