Breast cancer is the most frequently diagnosed cancer in women worldwide. Despite advances in early detection and treatment, a notable fraction of patients progress to metastatic disease where no cure exists. Accordingly, there is a pressing need for effective therapeutic strategies. Breast cancer arises primarily due to genetic or epigenetic alterations that aberrantly regulate oncogenes, tumor-suppressor genes or immune genes. While advantageous for cancer cell proliferation or immune-escape, these changes often make malignant cells vulnerable to attack by oncolytic herpes simplex (HSV). There is now increased recognition that dynamic virus-host interplay determines the magnitude of cell destruction or release of immunogenic factors. Preliminary studies suggest that recombinant HSV that lacks selected gene motifs efficiently replicates in and lyses cancer cells. Furthermore, it activates dendritic cells that are necessary to mediate adaptive antitumor immunity. We hypothesize that selectively engineered HSV may serve as a distinct anticancer platform, which destructs malignant cells meanwhile primes superior antitumor immunity. With state of the art technology, we will determine the therapeutic potency of oncolytic HSV in preclinical models. As such, we will systematically examine the antitumor activities exerted by genetically modified HSV. To achieve therapeutic synergy, we will integrate cyclic GAMP synthase, a key factor of innate immunity, into the oncolytic virus backbone. In addition, we will characterize its oncolytic efficacy in combination with an immune checkpoint blockade. Lastly, we will investigate the nature by which oncolytic HSV remodels the tumor microenvironment for antitumor responses. Collectively, these studies may facilitate the development of novel agents for breast cancer therapy.