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 is established and further modified with a novel anti-PD-L1 peptide JY4 for targeted delivery (DOX-SAR-JY4(LIPO)). The data here demonstrate that in a lung cancer xenograft mouse model, by facilitating the tumoral enrichment of both SAR405 and DOX, DOX-SAR-JY4(LIPO) effectively increases the infiltration of cytotoxic lymphocytes in the tumor by synergizing DOX-induced immunogenic cell death (ICD) and SAR405-mediated upregulation of chemokines including CCL5 and CXCL10. As results, DOX-SAR-JY4(LIPO) significantly inhibits tumor growth, metastasis, and resurrection by re-educating immunosuppressive tumor microenvironment. In conclusion, this 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.

Automated summary

Immunotherapy has revolutionized cancer treatment, but the low response rate remains a challenge, especially in cold tumors. A study introduces a tri-functional liposomal system, DOX-SAR-JY4(LIPO), which combines doxorubicin, a VPS34 inhibitor, and an anti-PD-L1 peptide for targeted delivery. This system effectively increases immune cell infiltration in lung cancer xenografts, inhibiting tumor growth and metastasis by reshaping the tumor microenvironment. The study demonstrates the potential of inhibiting autophagy and presents a promising approach to enhance cancer immunotherapy.