A STING agonist potentiates C1 lipidoid-based mRNA cancer vaccine through promoting TNF-α secretion in vivo

Intracellular delivery of antigen-encoding mRNA-based vaccine has shown great potential in the treatment of cancer and infectious diseases. We previously developed a minimalist cancer nanovaccine using C1 lipidoid nanoparticle with self-adjuvant activity, which markedly improves mRNA delivery and antigen presentation through TLR4 signaling activation. Although the C1-mRNA nanovaccine induced strong antitumor efficiency in prophylactic and therapeutic settings, it could not eliminate tumors with low immunogenicity. To further improve the therapeutic efficacy of the mRNA vaccine, we screened several innate immune receptor agonists and identified the STING agonist as an effective adjuvant for C1-mRNA vaccine, which could effectively promote the production of type I interferon and pro-inflammatory cytokines including IL-12 and TNF-α in dendritic cells. Such a C1-mRNA cancer vaccine adjuvanted with STING agonist effectively promoted antigen presentation in dendritic cells and enhanced T cell activation and exhibited strong antitumor activity on tumor models. Mechanistically, this mRNA vaccine showed improved antitumor efficacy largely depending on STING protein expression in dendritic cells and TNF-α induction in vivo, while type I interferon or IL-12 induction seemed dispensable. Together, by optimizing the antitumor efficacy of C1-mRNA cancer vaccine with STING agonist, this work provides a potential mRNA cancer vaccine platform for treating a wide range of tumor types.