Hydrogel-immobilized nanotherapeutics: Inhibition of protective autophagy to amplify STING signals for postsurgical tumor immunotherapy

Abstract

Activating the inherent stimulator of interferon gene (STING) pathway of cancer cells can inhibit tumor growth but can also induce protective autophagy of tumor cells to inhibit the STING-mediated immunotherapy. Therefore, amplification of STING activation and inhibition of autophagy could potentiate the cancer immunotherapy. Here, hydrogel-immobilized nanoparticles loaded with glucose oxidase (GOx), manganese ions (Mn2+) and hydroxychloroquine (HCQ) are prepared at the postsurgical site to enhance cancer therapy via activating the STING pathway and regulating the autophagy pathway. The delivered GOx and Mn2+ exert a chemo-dynamic therapy (CDT) to induce dsDNA damage, which can further initiate the STING pathway. HCQ can effectively inhibit protective autophagy associated with STING pathway activation, further amplify the antitumor immune responses. The synergistic delivery of CDT agents (i.e., GOx and Mn2+), STING agonists (i.e., Mn2+) and autophagy inhibitors (i.e., HCQ) results in a specific immune response, significantly inhibit tumor recurrence and metastatic tumor growth, which could extend the survival rate of mice suffered from the triple-negative breast cancer (TNBC).