Abstract
Endogenous retroviruses (ERV) are the genetic remnants of retroviruses in which proviral sequences integrated into germline cells of our ancestors. Although the vast majority of ERV sequences have accumulated mutations over the course of human evolution, some still contain open reading frames encoding full-length retroviral proteins. These sequences are typically epigenetically silenced in healthy adult human tissues. However, epigenetic dysregulation in cancer results in aberrant expression of ERVs in multiple cancer types. Therefore, ERVs represent a class of attractive therapeutic targets in cancer due to their immunogenicity and high expression in cancer cells compared with healthy tissues. In this review, we summarize the roles of ERVs in cancer and their immunogenicity, highlight the most recent advances in ERV-targeting strategies, discuss their challenges, and examine potential combination approaches that could further enhance the antitumor efficacy of ERV-targeting vaccines.