ABSTRACT In the United States, hepatocellular carcinoma (HCC) is the ninth leading cause of cancer mortality, with about 30,000 new liver cancer cases diagnosed annually. HCC disproportionately affects individuals from racial/minority populations including Asian Americans, Latinos, Native Americans and African Americans. CD46 (Cluster of differentiation 46) targeting oncolytic adenoviruses (OA) represents a promising novel therapeutic platform, given their low seroprevalence and high expression of CD46 in HCC, and ease of manipulation of OA genomes. The cGAS-STING pathway represents the major immune mechanism for neutralization of DNA viruses, including OAs. I propose the development and pre-clinical evaluation of recombinant oncolytic adenoviruses with increased potency in the setting of tumor selectivity in the treatment of hepatocellular cancer. Increased potency of vectors will be achieved through targeting and inhibiting the cGAS-STING pathway. This central tenet to the project is a very high reward in nature and if successful, has the potential to have a profound impact not only in HCC research but also will have broad application pertaining to novel therapies in other cancers where oncolytic vectors can be used. The proposed research and career development plan enclosed in this application would provide additional training and mentorship to enable me to progress toward becoming an independent investigator in the field of oncolytic virotherapy for advanced liver cancer. It would also provide substantial preliminary research that will serve as the basis for an R01 application to be submitted during the final year of the K01 award.