Intratumoral administration of mRNA encoding a fusokine consisting of IFN-ß and the ectodomain of the TGF-ß receptor II potentiates antitumor immunity.

It is generally accepted that the success of immunotherapy depends on the presence of tumor-specific CD8⁺ cytotoxic T cells and the modulation of the tumor environment. In this study, we validated mRNA encoding soluble factors as a tool to modulate the tumor microenvironment to potentiate infiltration of tumor-specific T cells. Intratumoral delivery of mRNA encoding a fusion protein consisting of interferon-ß and the ectodomain of the transforming growth factor-ß receptor II, referred to as Fß², showed therapeutic potential. The treatment efficacy was dependent on CD8⁺ T cells and could be improved through blockade of PD-1/PD-L1 interactions. In vitro studies revealed that administration of Fß² to tumor cells resulted in a reduced proliferation and increased expression of MHC I but also PD-L1. Importantly, Fß² enhanced the antigen presenting capacity of dendritic cells, whilst reducing the suppressive activity of myeloid-derived suppressor cells. In conclusion, these data suggest that intratumoral delivery of mRNA encoding soluble proteins, such as Fß², can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.