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bioRxiv · 10.1101/2025.09.16.676697

mRNA-Based Designer APCs Elicit Robust CD8⁺ and CD4⁺ T Cell Responses

Yamano, T.·Hanayama, R.·Le, T. V.·Imai, S.·Fujitsuka, I.·Ueda, M.·Nakamae, S.·Mizukami, S.
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Abstract

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 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 antigen, the co-stimulatory molecule CD80, and membrane-tethered IL-2. Administration of this mRNA mixture transforms somatic cells into designer antigen-presenting cells (APCs) in vivo, which simultaneously express the antigen, a co-stimulatory molecule, and a cytokine. These designer APCs more effectively activated tumor antigen-specific CD8 T cells than mRNA encoding the antigen alone and elicited robust anti-tumor immune responses. In addition, substituting IL-2 in the mRNA mixtures 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 both in human PBMCs in vitro and in HLA-A*02:01-transgenic mice, highlighting its translational potential. This modular mRNA strategy reprograms somatic cells in situ into designer APCs, providing a flexible and translatable platform for precision immunotherapy.

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Yamano, T., Hanayama, R., Le, T. V., Imai, S., Fujitsuka, I., Ueda, M., Nakamae, S., Mizukami, S.. 2025-09-19. mRNA-Based Designer APCs Elicit Robust CD8⁺ and CD4⁺ T Cell Responses. https://doi.org/10.1101/2025.09.16.676697

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