Light on dark matter: Epigenetic drugs as a tool to reveal the hidden antigen repertoire.

Cancer immunotherapy holds great promise in oncology, with personalized vaccines based on individual tumor antigens representing a cutting-edge approach in precision medicine. However, one of the challenges in implementing this approach lies in the limited number of tumor antigens in immunologically "cold" tumors. Recent studies have shown that the "dark matter"-comprising long non-coding RNAs, endogenous retroviruses, transposable elements, and aberrantly spliced transcripts-represents a significant source of hidden neoantigens that are normally epigenetically silenced. These transcripts can give rise to small peptides that are presented by MHC I molecules and trigger an immune response. Epigenetic drugs (epidrugs) can reshape the tumor transcriptome and activate "dark matter", which in turn expands the neoantigen repertoire. Targeted modulation of non-canonical transcripts with epidrugs could provide the basis for new immunotherapy platforms that leverage induced neoantigens.