Nanodrug Inducing Autophagy Inhibition and Mitochondria Dysfunction for Potentiating Tumor Photo-Immunotherapy

Abstract

Anticancer immunotherapy is hampered by the poor tumor immunogenicity and immunosuppressive tumor microenvironment (TME). Herein, a liposome nanodrug co-encapsulating doxycycline hydrochloride (Doxy) and chlorin e6 (Ce6) to simultaneously induce autophagy inhibition and mitochondria dysfunction for potentiating tumor photo-immunotherapy is developed. Under near infrared laser irradiation, Ce6 generates cytotoxic reactive oxygen species (ROS) and elicits robust photodynamic therapy (PDT)-induced immunogenic cell death (ICD) for immunosuppressive TME remodeling. In addition, Doxy induced mitochondria dysfunction, which increases ROS generation and enhances PDT to exert more potent killing effect and more powerful ICD. Meanwhile, Doxy increases MHC-I expression on tumor cells surface by efficient autophagy inhibition, leading to more efficient antigen presentation and CTLs recognition to increase tumor immunogenicity. The nanodrugs elicit remarkable antitumor therapy by combining Ce6-mediated PDT and Doxy-induced autophagy inhibition and mitochondria dysfunction. The developed nanodrugs represent a highly efficient strategy for improving cancer immunotherapy.

Keywords: autophagy inhibition; combination therapy; mitochondrial dysfunction; nanodrugs; photo-immunotherapy.