A Novel Tri-Functional Liposome Re-Educates "Cold Tumor" and Abrogates Tumor Growth by Synergizing Autophagy Inhibition and PD-L1 Blockade

by Selleckchem | Jun 22 2023

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-JY4LIPO ). The data here demonstrate that in a lung cancer xenograft mouse model, by facilitating the tumoral enrichment of both SAR405 and DOX, DOX-SAR-JY4LIPO 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-JY4LIPO 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.

Comments:

The study describes the development and evaluation of a novel liposomal system called DOX-SAR-JY4LIPO for cancer immunotherapy. The system combines the chemotherapy drug doxorubicin (DOX) with a highly specific VPS34 inhibitor called SAR405, and is further modified with an anti-PD-L1 peptide called JY4 for targeted delivery.

The researchers aimed to convert "cold tumors," which are solid tumors with low immune cell infiltration, into "hot tumors" that are more responsive to immunotherapy. They hypothesized that by inhibiting autophagy with SAR405, they could enhance immune cell infiltration into the tumor. Additionally, they expected that DOX-induced immunogenic cell death (ICD) would further promote an immune response against the tumor.

To evaluate the efficacy of the DOX-SAR-JY4LIPO system, the researchers conducted experiments using a lung cancer xenograft mouse model. The results showed that the liposomal system effectively increased the infiltration of cytotoxic lymphocytes into the tumor. This effect was attributed to the synergistic action of DOX-induced ICD and SAR405-mediated upregulation of chemokines, specifically CCL5 and CXCL10, which are involved in immune cell recruitment.

Furthermore, DOX-SAR-JY4LIPO demonstrated significant inhibition of tumor growth, metastasis, and recurrence. It achieved this by re-educating the immunosuppressive tumor microenvironment, essentially creating a more favorable immune response against the tumor.

In conclusion, this study supports the concept of inhibiting autophagy to enhance immune cell infiltration in "cold tumors." Moreover, the development of the tri-functional liposomal system, DOX-SAR-JY4LIPO, addresses the limitations of current therapies and holds promise for cancer immunotherapy. However, it's important to note that this study represents a specific research finding and further investigations and clinical trials are necessary to fully validate the potential of this approach in treating cancer patients.