Overcoming immune resistance by sequential prodrug nanovesicles for promoting chemoimmunotherapy of cancer

Abstract

Chemotherapy by certain types of anticancer drugs (e.g., doxorubicin (DOX) and oxaliplatin (OXA)) can elicit antitumor immune response by promoting immunogenic cell death (ICD) of the tumor cells. However, ICD-based chemoimmunotherapy is severely impaired by non-specific distribution of the chemotherapeutics and T lymphocyte-induced immune resistance. To address these challenges, we herein reported a sequential prodrug nanovesicle specifically designed for enhancing drug delivery to the tumor tissues and reducing the immunological resistance of the tumor cells. The prodrug nanovesicles were composed of fluorophore IR-1061, chemotherapeutic DOX, and a prodrug of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Upon 1064 nm laser irradiation, IR-1061 induced mild hyperthermia for triggering NIR-Ⅱ fluorescence imaging-guided drug release at the tumor site. DOX promoted intratumoral infiltration of the cytotoxic T lymphocytes (CTLs) by inducing ICD of the tumor cells. Meanwhile, JQ1 blocked IFN-γ-induced upregulation of programmed death ligand 1 (PD-L1) to reduce the adaptive immune resistance. In combination with laser irradiation, the prodrug nanovesicles remarkably inhibited growth of both 4T1 breast and CT26 colorectal tumors, and suppressed lung metastasis of 4T1 breast tumor in the immunocompetent mouse model. The prodrug nanoplatform reported herein might provide a novel insight for promoting chemoimmunotherapy of cancers by overcoming PD-L1-dependent immune evasion through the IFN-γ-BRD4-PD-L1 axis.