Combined cancer immunotherapy with lipid nanoparticle delivery of oligo-based cGAS-agonistic adjuvant and peptide or mRNA vaccines.

Therapeutic vaccines are promising for cancer immunotherapy in combination with immune checkpoint blockade (ICB). Though lipid nanoparticles (LNPs) hold great potential to deliver cancer therapeutic vaccines, LNPs delivering peptide or mRNA vaccines often induce suboptimal T cell responses. Type I interferon (IFN-I) responses can enhance antigen presentation and potentiate T cell responses. Here, we report LNP codelivery of peptide or mRNA vaccines with a cyclic GMP-AMP synthase (cGAS) agonist that can specifically induce IFN-I responses to potentiate anticancer T cell responses for robust ICB combination immunotherapy of tumors. Svg3, an oligonucleotide-based cGAS agonist, can be efficiently coloaded with antigenic peptides or antigen-encoding mRNAs into LNPs and codelivered to mouse draining lymph nodes and antigen-presenting cells (APCs). Svg3 promoted the antigen presentation and antigen-specific CD8(+) T cell responses in mice. The combination of LNP-delivered Svg3 with peptide or mRNA encoding antigens promotes anti-tumor responses, reduces immune suppression, and enhances tumor therapeutic efficacy when combined with ICB.