Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications.

Endogenous retroviruses (ERVs) are epigenetically silenced remnants of ancient retroviral integrations that comprise ~8% of the human genome. In cancer, DNA hypomethylation and chromatin remodeling-spontaneously or induced by epigenetic therapies-can derepress ERV loci, leading to abundant ERV-derived double-stranded RNA (dsRNA) and, in some cases, immunogenic ERV proteins. Accumulated dsRNA is primarily sensed by MDA5/RIG-I and TLR3, activating MAVS/TRIF signaling to induce IRF3/7- and NF-κB-dependent type I interferons and interferon-stimulated genes. This viral mimicry enhances antigen processing and MHC-I presentation, recruits CXCR3+ effector lymphocytes via CXCL9/10/11, promotes dendritic-cell activation, reduces immunosuppressive populations, and can convert immune-cold tumors into immune-active states while also increasing PD-L1 expression. Clinical evidence from retrospective cohorts and early prospective studies supports ERV signatures as biomarkers for immune checkpoint inhibitor (ICI) response, often independent of PD-L1 or tumor mutational burden, and enables ERV-based stratification. Therapeutic strategies that induce ERVs or target ERV antigens may sensitize tumors to ICIs, although assay standardization, prospective validation, and long-term safety remain key challenges.