Simple SummaryEndogenous retroviruses (ERVs) are integrated retroviral elements that cover 8% of the human genome, representing thereby four-fold the fraction of the genome encoding for protein-coding genes. Overall, their expression represents up to 0.5% of all non-rRNA transcripts in mesothelioma, and some are specifically re-activated. This part of the genome has been considered until recently “junk DNA” or “DNA dark matter”. However, analysis of ERV expression has recently gained attention in several cancers, especially in the context of immunotherapy. In this review, our aim is to raise the curiosity of non-specialists by illustrating the potential of exploring the expression of “DNA dark matter” for prognosis and immunotherapy, potentially as predictive biomarkers in mesothelioma.AbstractRecent high-throughput RNA sequencing technologies have confirmed that a large part of the non-coding genome is transcribed. The priority for further investigations is nevertheless generally given in cancer to coding sequences, due to the obvious interest of finding therapeutic targets. In addition, several RNA-sequencing pipelines eliminate repetitive sequences, which are difficult to analyze. In this review, we shall focus on endogenous retroviruses. These sequences are remnants of ancestral germline infections by exogenous retroviruses. These sequences represent 8% of human genome, meaning four-fold the fraction of the genome encoding for proteins. These sequences are generally mostly repressed in normal adult tissues, but pathological conditions lead to their de-repression. Specific mesothelioma-associated endogenous retrovirus expression and their association to clinical outcome is discussed.