A pro-death autophagy-based nanoplatform for enhancing antitumour efficacy with improved immune responses

Abstract

Due to the pro-survival effect of mild autophagy, the therapeutic effect of chemo-immunotherapy is unsatisfactory. In addition, the adverse tumour microenvironment (TME), including the lack of antigen presentation, the deficiency of oxygen supply and immunosuppressive cells, results in immune escape and metastasis. Herein, a novel nanoplatform (CS-3BP/PA@DOX) based on the autophagy cascade is proposed for the first time to deliver the chemotherapeutic doxorubicin (DOX) and respiration inhibitor 3-bromopyruvic acid (3BP) to overcome the above obstacles. CS-3BP/PA@DOX exerts a synergistic therapeutic effect to initiate pro-death autophagy and facilitate the antigen presentation process by combining DOX chemotherapy and starvation therapy with 3BP. Additionally, CS-3BP/PA@DOX remodelled the immunosuppressive TME by alleviating hypoxia, damaging dense ECM, and downregulating PD-L1 to enhance antitumour immunity. 3BP was found to promote GSH depletion by inhibiting respiration for the first time, which reduces the chemical resistance of cancer and increases the sensitivity of cells to ROS, providing a new therapeutic direction of 3BP for antitumour treatment. Collectively, this study offers an opportunity to magnify pro-death autophagy, augment antitumour efficacy, facilitate anti-metastatic effects, and boost immune responses.

Keywords: Apoptosis; Chemoimmunotherapy; Hypoxia; Pro-death autophagy; Tumour microenvironment.