Control of poorly immunogenic tumors with systemic STING agonist-loaded liposomes targeting cross-presenting dendritic cells.

Objectives: Cancer vaccines combine tumor antigen and adjuvant to drive an anti-tumor immune response. Clec9A-targeted nanoparticles directing CD4 and CD8 neo-epitopes to cross-presenting dendritic cells (DCs) stimulate adjuvant-free therapeutically effective tumor-specific immunity. However, personalised neo-epitopes limit the scalability of Clec9A nanoparticles for clinical translation. Since Clec9A Methods: Liposomes encapsulating RIG-I or the STING agonist MSA-1 and functionalised with Clec9A binding peptide WH were optimised for uptake by Clec9A Results: Clec9A-targeting liposomes administered i.v. were distributed to spleen, liver and tumor and were taken up by cross-presenting and plasmacytoid DCs. Type 1 IFN production and DC, B- and T-cell activation were more effective with i.v. Clec9A-STING than Clec9A-RIG-I liposomes. Intravenous Clec9A-STING liposomes stimulated IFN-dependent transcription in blood, lung, tumor, and draining lymph nodes. Intravenous Clec9A-STING liposomes, or intra-tumoral Clec9A-RIG-I liposomes significantly suppressed B16-F10 melanoma growth and induced neo-epitope and survivin-specific CD4 Conclusions: Clec9A-STING liposomes are a scalable, translatable tumor-targeted immunotherapy platform.