A major breakthrough in cancer immunotherapy is the identification of non-canonical cancer antigens—tumor-specific targets derived from the dark genome and other unconventional sources. These antigens often evade central tolerance, may have tumor promoting functions, and be shared across cancer types, making them attractive for both vaccine and adoptive T cell therapies. They arise from previously overlooked genomic elements such as non-coding RNAs (lncRNAs, circRNAs, UTRs), out-of-frame translations, gene fusions, recurrent mRNA mis-splicing events, ERE, and HERV. Once considered biologically irrelevant, these sequences are now known to produce peptides presented on HLA molecules and be recognized by T cells. In this session, speakers will describe novel classes of cancer antigens that result from diverse molecular mechanisms which extend beyond simple point mutations. Finally, the actionability of these novel HLA-restricted non-canonical peptides will be highlighted using studies of T cell immunogenicity, active immunization, and TCR gene transfer.