Breast cancer (BC) is the most commonly diagnosed cancer in women, a leading cause of cancer related death in the United States and remains a major oncological problem global. Triple-negative BC (TNBC), is a more aggressive clinical subtype with high incidence rate and mortality, and dampened response to chemotherapies. Oncolytic viruses (OVs) can selectively infect, replicate and eradicate cancer cells with defective type I interferons (IFNs) mechanisms, a major antiviral pathway. Herpes-based OVs epitomize a hopeful and innovative anti-cancer strategy and a substantial benefit of HSV-1 is its large genome size (~152kbp), having modifiable accessory genes that allow for genes to be deletion or insertion with the goal to enhance antitumor immune responses. Therefore, it can be engineered to not initiate a productive infection in healthy cells. In cancer, dysregulated IFNs and signaling pathway like the PI3K/Akt/mTOR cooperate in tumorigenesis related to many cancer types, including BC. The PI3K/AKT/mTOR signaling pathway is a crucial survival regulator of cellular stress and helps balance protein synthesis, cell cycle, and apoptosis to ensure the survival of resilient tumor cells. Moreover, PI3K or AKT inhibition diminishes cells' IFN-Is signatures. Therefore, we hypothesize that local inhibition of the cancer molecular targets and PI3K/AKT/mTOR signaling pathway in the tumors will create a conducive environment for the intratumoral replication and spread of oncolytic HSV-1 and virus-induced cancer cell death resulting in tumor growth delay and extended survival in a stage four metastatic mouse model of BC. Because of the adverse effects associated with HSVs, we have constructed a novel hybrid VC2-GMCSF recombinant virus (VC2-G), where the HSV-1 gC gene in VC2 is replaced with that of murine GMCSF gene under the human cytomegalovirus (HCMV) immediate early promoter to improve their safety and potency. We recently identified fisetin, a natural compound, and two of its potent derivatives, as inhibitors of the mTOR/AKT/IFN pathway targets. Furthermore, published and our preliminary data show increased sensitivity and cytotoxicity of cancer cells to oncolytic virus upon pre-therapy with small molecules while sparing normal cells. Thus, we expect that locally modulating dysregulated cancer targets with fisetin and other small molecules to enhance oncolytic viral replication and spread can serve as a novel pharmaco-virotherapy for advanced localized BC like TNBC. Our aims are designed to test this innovative hypothesis in cell lines and preclinical animal models of BC by 1) Determining the mechanism by which fisetin/analogs modulate mTOR and type I IFN pathway antiviral responses and other cancer targets in cultured BC cells, and 2) Determining whether pre-therapy with fisetin/analogs or signaling axis inhibitors can maximize the anti-tumor efficacy of oncolytic VC2-G in BC in vivo. Furthermore, our approach may lead to new opportunities for synergistic or additive combinations with other therapies to improve OVs therapeutic efficacy and safety.