Endogenous retroviruses in development, immunity, and disease: From regulatory roles to therapeutic opportunities

Endogenous retroviruses (ERVs), representing nearly 8% of the human genome, have transitioned from ancient viral remnants to pivotal regulators of host biology. Once integrated into germline DNA, ERVs accumulated sequence divergence and epigenetic silencing, yet many retained functional long terminal repeats (LTRs) and protein-coding genes that were repurposed for host development, immunity, and genome regulation. Recent studies reveal that ERVs act as lineage-specific enhancers, promoters, and RNA regulators, orchestrating processes ranging from embryonic cell fate decisions to antiviral defense. Dysregulation of ERVs, however, drives diverse pathologies, including oncogenesis, autoimmunity, neurodegeneration, and microbiota-immune imbalance. Mechanistically, ERVs reactivation shapes tumor microenvironments, induces chronic inflammation, and contributes to epigenetic instability during aging. These insights have sparked growing interest in ERVs as diagnostic biomarkers and therapeutic targets. Epigenetic drugs exploiting ERVs reactivation for "viral mimicry" immunotherapy, CRISPR-based strategies for targeted ERV silencing, and ERV-derived neoantigens for precision oncology exemplify emerging translational avenues. Future integration of single-cell omics, genome editing, and immunogenomics promises to elucidate ERVs regulatory networks and accelerate the development of ERV-centered diagnostics and therapeutics. Collectively, ERVs embody a molecular nexus linking evolution, development, immunity, and disease, offering transformative potential for precision medicine.