cGAS mRNA-based Immune Agonist Promotes Vaccine Responses and Antitumor Immunity.

mRNA vaccines are recognized as potent tools for immunization against viral diseases and cancer. However, the lack of a vaccine adjuvant limits the efficacy of these treatments. Here, we used cGAS mRNA, which encodes the DNA innate immune sensor, complexed with lipid nanoparticles (LNPs) to boost the immune response. By introducing specific mutations in human cGAS mRNA (hcGASK187N/L195R), we significantly enhanced cGAS activity, resulting in a more potent and sustained STING-mediated interferon (IFN) response. cGAS mRNA-LNPs exhibited stimulatory effects on maturation, antigen engulfment and antigen presentation by antigen-presenting cells (APCs) both in vitro and in vivo. Moreover, the hcGASK187N/L195R mRNA-LNP combination has shown a robust adjuvant effect, amplifying the potency of mRNA and protein vaccines by inducing strong humoral and cell-mediated responses. Remarkably, the hcGASK187N/L195R mRNA-LNP complex, either alone or in combination with antigens, demonstrated exceptional efficacy in eliciting antitumor immunity. In addition to its immune-boosting properties, hcGASK187N/L195R mRNA-LNP exerted synergistic antitumor effects with IFNγ directly on tumor cells, further promoting tumor restriction. In conclusion, we developed a cGAS-mRNA-based immunostimulatory adjuvant compatible with various vaccine forms to boost the adaptive immune response and cancer immunotherapies.