Endogenous retroviruses in aging and cancer: from genomic defense to oncogenic activation

Nearly half of the human genome consists of transposable elements, among which endogenous retroviruses, remnants of ancient retroviral infections, represent some of the most evolutionarily intriguing due to their paradoxical functional duality. While research has documented functional ERV exaptation in key biological processes, these elements have also been associated with age-related diseases, particularly cancer. This apparent contradiction presents an evolutionary question: why would potentially disruptive elements persist in genomes over evolutionary time? Here we review the complex relationship between ERVs, aging and cancer to address this question. After reviewing the physiological roles of ERVs, we explore how the transcriptional activation of normally repressed ERVs may function as an evolutionary-conserved genomic surveillance system that, when triggered by cellular stressors, generates viral-like nucleic acids and proteins that activate pathways to potentially eliminate cancerous cells. Conversely, we discuss how cancer cells could appropriate ERV expression to distort cellular processes, promoting inflammation and senescence that ultimately facilitate tumor progression. Despite this duality, we advance a novel hypothesis that many ERVs have been exapted in mammalian genomes primarily as defense mechanisms against tumorigenesis. This evolutionary perspective provides a framework for understanding both the persistence of ERVs in our and other mammals' genomes and their intriguing roles in cancer biology. Moreover, even after tumor development, ERVs can be exploited by immunotherapy due to their canonical function as regulators of the immune response, positioning them as emerging central elements in cancer treatment strategies. This work offers new insights into these endogenous retroviruses' evolutionary significance and potential applications in cancer therapeutics and diagnostics.