{"doi":"10.3389/fimmu.2026.1835325","title":"Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications","abstract":"<jats:p>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.</jats:p>","journal":"Frontiers in Immunology","year":2026,"id":651207,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1698238,"name":"Quezhu Danzeng","orcid":null,"position":1,"is_corresponding":false},{"id":1698239,"name":"Runxi Wu","orcid":null,"position":2,"is_corresponding":false},{"id":456227,"name":"Yi Shen","orcid":"0000-0001-5043-5211","position":3,"is_corresponding":false},{"id":570319,"name":"Guang Shi","orcid":"0000-0002-4377-7210","position":4,"is_corresponding":false},{"id":1698237,"name":"Fanyuan Wu","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications","abstract":"<jats:p>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.</jats:p>","is_dataset_classified":null,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"42245637","pmcid":"PMC13230102","openalex_id":"https://openalex.org/W7161829956","authors":[],"funders":[],"total_grants":0,"fwci":6.6027,"citation_percentile":0.9673559,"influential_citations":0,"citation_trend":[{"year":2026,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1835325/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2026.1835325/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fimmu.2026.1835325/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fimmu.2026.1835325","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/42245637","host_type":"repository"},{"url":"https://doaj.org/article/a75b49c658d5407abeb2abb086a834ca","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC13230102/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC13230102","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC13230102?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Chromosomal and Genetic Variations","Viral-associated cancers and disorders","interferon and immune responses","Humans","Endogenous Retroviruses","Immune Checkpoint Inhibitors","Neoplasms","Animals"],"mesh_terms":["Immune Checkpoint Inhibitors","Animals","Humans","Neoplasms","Endogenous Retroviruses"],"keywords":["Endogenous retrovirus","Epigenetics","Chromatin","Immune system","Effector","Immune checkpoint","Endogeny","DNA methylation","Antigen","Immunotherapy","Epigenetic regulation","Endogenous retroviruses","Tumor Microenvironment","Immune Checkpoint Inhibitors","Viral Mimicry"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-10T06:50:16.878268Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}