Human endogenous retroviruses in liver cancer: A double-edged sword in tumor progression and anti-tumor immunity.

Hepatocellular carcinoma (HCC) ranks among the most prevalent and lethal malignancies worldwide. The majority of patients are diagnosed at advanced stages, where current targeted therapies benefit only a subset of patients. Consequently, there is a pressing need to identify novel therapeutic targets and develop corresponding treatment strategies. Human endogenous retroviruses (HERVs), which constitute approximately 8% of the human genome, represent remnants of ancient viral infections and have been increasingly implicated in cancer pathogenesis. In HCC, HERVs exhibit a significant "double-edged sword" characteristic in the occurrence and development of cancer, having both oncogenic and tumor-suppressive effects. On the one hand, the oncogenic mechanisms mainly involve oncogenic lncRNAs derived from HERVs, the formation of virus-like particles, and the regulation of oncogene expression as alternative promoters/enhancers. On the other hand, the tumor-suppressive effects are achieved through mechanisms such as viral mimicry activating antiviral pathways, the production of tumor-suppressive lncRNAs, and the presentation of tumor-specific neoantigens. This review will systematically elucidate the bidirectional regulatory mechanisms of HERVs in liver cancer and explore future research directions in the field of HERV-related liver cancer.