Liposome-like Nanoplatform Regulates Autophagy to Enhance Antitumor Chemo-Immunotherapy

Abstract

Studies on immunogenic cell death of tumor cells have confirmed that some chemotherapy drugs can induce antitumor immune response. This immune response is caused by the tumor antigens released by dead cells. However, these tumor antigens and damage-associated molecular patterns (DAMPs) can be degraded by the autophagy pathway, which is highly upregulated in tumor cells. Studies have shown that the inhibition of autophagy can increase the accumulation of autophagosomes, reduce the degradation of tumor antigens and major histocompatibility complex (MHC) class I molecules, and maintain or even enhance immune responses. In order to enhance the chemotherapy-induced antitumor immune response through the regulation of autophagy, this project intends to create a nanoplatform for the codelivery of chemotherapeutics and autophagy inhibitors. Phospholipid-modified autophagy inhibitor DSPE-BiQ and chemotherapy drug DSPE-OXA-PEG were synthesized, respectively, and the generated codelivery system OXA/BiQ-Lip could achieve efficient drug delivery and release through the EPR effect and the stimulation from intracellular pH gradient/reduced glutathione concentration changing. The codelivery strategy of autophagy inhibitors and chemotherapeutics could not only overcome oxaliplatin drug resistance but also promote the accumulation of intact autophagosomes containing multiple tumor antigens and DAMPs, enhance antigen presentation and immune cells infiltration, and improve the antitumor immune response triggered by chemotherapy.