A Novel Tri‐Functional Liposome Re‐Educates “Cold Tumor” and Abrogates Tumor Growth by Synergizing Autophagy Inhibition and PD‐L1 Blockade

Abstract 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.