A Novel Tri-functional Liposome Re-educates "Cold Tumor" and Abrogates Tumor Growth by Synergizing Autophagy Inhibition and PD-L1 Blockade.

Immunotherapy has been regarded as a breakthrough in cancer treatment and achieved great success. However, the poor response rate is still a formidable challenge of current immunotherapies, especially in solid tumors without sufficient infiltration of immune cells, also known as "cold tumor". SAR405 is a highly specific VPS34 inhibitor and has been suggested as a potential approach converting "cold tumor" into "hot tumor" by inhibiting autophagy. In this study, a tri-functional doxorubicin (DOX) plus SAR405 liposome system was established and further modified with a novel anti-PD-L1 peptide JY4 for targeted delivery (DOX-SAR-JY4 LIPO ). Our data demonstrated that in lung cancer xenograft mouse model, by facilitating the tumoral enrichment of both SAR405 and DOX, DOX-SAR-JY4 LIPO effectively increased the infiltration of cytotoxic lymphocytes in the tumor by synergizing DOX-induced immunogenic cell death and SAR405-mediated upregulation of chemokines including CCL5 and CXCL10. As results, DOX-SAR-JY4 LIPO significantly inhibited tumor growth, metastasis and resurrection by re-educating immunosuppressive tumor microenvironment. In conclusion, our study not only proves the concept of inhibiting autophagy for better immune infiltration in the tumor but also presents a novel tri-functional liposomal system that overcomes the deficiencies of current therapies and holds great promise in cancer immunotherapy. This article is protected by copyright. All rights reserved.