Recently, we have demonstrated that a novel RNA origami (RNA-OG) nanostructure functions as a TLR3 agonist both in vitro and in vivo. This RNA nanostructure could induce effective antitumor immunity in a CT26-OVA-iRFP tumor model that expresses both ovalbumin (OVA) and near infrared protein (iRFP), rendering a significant delay in tumor growth or complete tumor-regression. However, in a similar tumor line that expresses iRFP but not OVA, i.e. a CT26-Neo-iRFP model, RNA-OG induced responses that were consistently inferior to those observed in CT26-OVA-iRFP. Interestingly, the antitumor immunity initially generated against CT26-OVA-iRFP was found to render the mice immune to a challenge with the more malignant CT26-Neo-iRFP line. In addition to OVA expression, the two cell lines also showed different levels of MHC-I. Ongoing research has been focused on deciphering the molecular nature of the different responses. Then, we can search for strategies that increase the tumor immunogenicity, and therefore improve the therapeutic efficacy of RNA-OG for inducing long-term tumor-regression.