An mRNA vaccine elicits STING-dependent antitumor immune responses

Lipid-formulated RNA vaccines have been widely used for disease prevention and treatment, yet their mechanism of action and individual components contributing to such actions remain to be delineated. Here, we show that a therapeutic cancer vaccine composed of a protamine/mRNA core and a lipid shell is highly potent in promoting cytotoxic CD8+ T cell responses and mediating anti-tumor immunity. Mechanistically, both the mRNA core and lipid shell are needed to fully stimulate the expression of type I interferons and inflammatory cytokines in dendritic cells. Stimulation of interferon-β expression is exclusively dependent on STING, and antitumor activity from the mRNA vaccine is significantly compromised in mice with a defective Sting gene. Thus, the mRNA vaccine elicits STING-dependent antitumor immunity. The mRNA vaccine particle (MVP) uptake by DC triggers expression of IFN-β and TNF-α through STING and MAVS dependent pathways, respectively. T cells are subsequently primed, leading to antigen-specific cancer cell killing and tumor eradication. [Display omitted]