Liver cancer is the fifth most frequently diagnosed cancer world-wide and is the second leading cause of cancer death in men. The current treatments for Hepatocellular Carcinoma (HCC), the most common type of liver cancer, are gradually shifting from systemic anti-cancer drugs to immunotherapeutic agents, mainly immune checkpoint inhibitors (ICIs). Although ICIs are very promising, they are active in a small fraction of patients, inducing durable remissions in only 1-5% of responding patients. Therefore, combinations with other systemic or local treatments are perceived as the most promising opportunities in HCC. An additional hurdle for combinatorial immunotherapeutic intervention is that many systematically applied anti-cancer drugs can dampen the anti-tumor immune response due to drug induced side effects.

We hypothesized that anti-cancer drugs which induce immunogenic cell death (ICD) can effectively synergize with ICIs when they are self-assembled in tumor targeted nanoparticles (NPs), sparing immune cells from cytotoxicity and systemic side effects. Previous work showed that a subset of sulfated indocyanine dyes can self-assemble with hydrophobic drugs to form stable NPs with high drug loading that can be effectively delivered to liver tumors in mice. In this thesis, we identified and precipitated new drug candidates with novel dye stabilizers in NPs to combine with ICIs. We evaluated their efficacy in vitro using novel 3D co-culture models developed in the lab and in vivo biodistribution and efficacy using immunocompetent autochthonous murine liver cancer models.