With the end of improving patient response and prognosis in hepatocellular carcinoma (HCC), we propose a combined therapy using checkpoint inhibitors and immunotherapeutic anti-cancer vaccination. In search for alternative sources of antigens, we focused on long non-coding RNAs (lncRNAs) which, in spite of their name, may encode for microproteins. In addition, certain lncRNAs are highly cancer-specific and not expressed in healthy tissues. This should permit the use of microproteins derived from these lncRNAs as potential immunogenic antigens for anticancer vaccination. To prove this hypothesis, we selected HCC specific lncRNAs with high expression and translation potential as demonstrated through ribosome profiling and qRT-PCR. Using this collection, we identified epitopes with high HLA class I/II binding affinity using in silico and in vitro studies. Subsequent immunization studies supported the epitopes’ ability to generate an in vivo immunogenic response. Furthermore, we generated alphavirus-based recombinant vectors that transcribe for auto-replicative RNA molecules expressing the antigens of interest. These systems were used to evaluate the effects of different vaccination platforms. Results showed that intradermal administration and electroporation of a recombinant DNA plasmid expressing the antigens from the SFV system, yielded comparable results to that of SFV viral particles, demonstrating high immunogenicity, particularly in the case of class II peptides. Further studies will be devoted to generate self-amplifying RNAs expressing the selected microproteins in tandem, which will be delivered to patients into a lipid nanoparticle carrier as an adjuvant for immune checkpoint inhibitor therapies.