Modular mRNA cocktail enables synergistic activation of antigen-specific T cells for cancer immunotherapy.

mRNA-based therapeutics have demonstrated notable success in SARS-CoV-2 vaccines and are emerging in cancer immunotherapy. However, conventional mRNA cancer vaccines are limited in part by the low immunogenicity of tumor-associated and neoantigens. We addressed this limitation by formulating a modular, liposome-based mRNA cocktail comprising three distinct mRNAs encoding tumor antigens, the co-stimulatory molecule CD80, and membrane-tethered IL-2. Administration of this mRNA cocktail resulted in synergistic activation of tumor antigen-specific CD8⁺ T cells and robust anti-tumor immune responses. In addition, substituting IL-2 in the mRNA cocktail with membrane-tethered IL-12 led to the expansion and differentiation of endogenous antigen-specific Th1 helper T cells in vivo. Importantly, this platform activated NY-ESO-1-specific CD8⁺ T cells in HLA-A*02:01-transgenic mice, highlighting its translational potential. This modular mRNA cocktail provides a flexible and translatable platform for precision cancer immunotherapy by enabling coordinated activation of both CD8⁺ and CD4⁺ T cell responses.