Endogenous viruses are “ancient” viruses that have coevolved with their host species for millions of years, developing strategies to maintain an equilibrium state with their host. In particular, human endogenous retroviruses (HERVs) are permanently integrated and make up over 8% of our genome. Recent studies have shown that the equilibrium between these endogenous retroviruses and our cells can be broken in several conditions, including cancer. HERV reactivation in cancer cells may result in (a) the activation of a viral defense response against cancer, (b) the production of viral proteins that can be recognized as targets by our immune system and (c) the expression of viral transcripts that can be used as therapeutic targets or markers for prognosis. Overall, this may positively impact on cancer immunotherapy strategies.

Human endogenous retroviruses (HERVs) derive from ancestral exogenous retroviruses whose genetic material has been integrated in our germline DNA. Several lines of evidence indicate that cancer immunotherapy may benefit from HERV reactivation, which can be induced either by drugs or by cellular changes occurring in tumor cells. Indeed, several studies indicate that HERV proviral DNA can be transcribed either to double-stranded RNA (dsRNA) that is sensed as a “danger signal” by pattern recognition receptors (PRRs), leading to a viral mimicry state, or to mRNA that is translated into proteins that may contribute to the landscape of tumor-specific antigens (TSAs). Alternatively, HERV reactivation is associated with the expression of long noncoding RNAs (lncRNAs). In this review, we will highlight recent findings on HERV reactivation in cancer and its implications for cancer immunotherapy.