Development mitochondrial destabilizing polypeptide inducing immunogenic cell death for enhanced cancer immunotherapy

Abstract

Immunogenic cell death (ICD) has been emerging as a new aspect of cancer therapy. In order to induce effective ICD, high levels of the release of damage-associated molecular patterns (DAMPs) are required. For inducing ICD most effectively, stress induction in endoplasmic reticulum (ER) and generation of reactive oxygen species in the of cancer cells plays a pivotal role. However, depending on the drug, ER stress induction or reactive oxygen species production may occur independently, which reduces the degree of immunogenic cell death. In addition, in the case of representative anticancer drugs, such as doxorubicin and camptothecin, the limitations of drug delivery in the body due to hydrophobicity are also clear. In this study, we developed a mitochondrial destabilizing polypeptide (MDP) which of side branches was modified with mitochondrial targetable chemical group. This polypeptide has a permanent positive charge on the side branches, which provides amphiphilicity to the polypeptide and induces mitochondrial membrane instability due to its membrane permeability through the alpha helix structure. Through these properties, it was confirmed that the MDPs can induce mitochondrial ROS and calcium ion release, and simultaneously cause intracellular ER stress and ROS production. We confirmed the inducing of ICD through the release of various DAMPs by MDPs were confirmed. This study suggested that developed novel polypeptides, MDPs, can be used as a novel anticancer agent that can be used independently on a drug delivery platform, and at the same time, and it is expected the possibility of overcoming immunosuppressive tumor microenvironment.