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Their pathognomonic reactivation across malignancies orchestrates tumorigenesis through three interconnected molecular axes: (1) genomic destabilization via LTR-mediated insertional mutagenesis, disrupting key loci such as\n                    <jats:italic>TP53<\/jats:italic>\n                    and\n                    <jats:italic>MYC<\/jats:italic>\n                    ; (2) immune checkpoint subversion, driven by HERV-K envelope glycoprotein-induced PD-L1 upregulation (2.3-fold;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01); and (3) chronic inflammatory signaling triggered by double-stranded RNA (dsRNA) activation of innate immune pathways (TLR3\/MDA5\/NLRP3). This foundational mechanistic insight is accelerating clinical translation. Diagnostic advances now feature HERV-K Env-targeted liquid biopsies achieving 92% specificity (AUC\u2009=\u20090.94) for early-stage tumors and artificial intelligence (AI)-enhanced platforms (e.g., DeepHERV, AUC\u2009=\u20090.91) that resolve complex HERV expression landscapes. Therapeutically, an emerging pipeline of strategies is rapidly advancing, from initial first-in-human clinical trials (NCT05687903, NCT05554866) of HERV-directed monoclonal antibodies and vaccines to the highly promising preclinical efficacy demonstrated by HERV-K-specific chimeric antigen receptor (CAR) T-cells (&gt;\u200970% tumor regression) and locus-precise CRISPR\/Cas9 epigenetic silencing. However, clinical translation is complicated by persistent challenges, including intratumoral HERV heterogeneity, a lack of assay standardization (as evidenced by 60% primer discordance), and the fundamental ethical and therapeutic requirement for specificity\u2014that is, precise discrimination between pathogenic HERVs and their essential physiological counterparts. A convergent translational framework\u2014leveraging international consortia for biomarker validation, machine learning for patient stratification, and engineered tumor-selective delivery platforms\u2014is now positioned to harness this novel target class and redefine the next era of precision oncology.\n                  <\/jats:p>","DOI":"10.1007\/s12672-026-04709-7","type":"journal-article","created":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T05:33:32Z","timestamp":1776317612000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mechanisms biomarkers and therapeutic strategies of human endogenous retroviruses in cancer"],"prefix":"10.1007","volume":"17","author":[{"given":"Alfred","family":"Ndjekadom","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lichen","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenglin","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaochun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Likai","family":"Ji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongling","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongfeng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"issue":"1","key":"4709_CR1","first-page":"1","volume":"16","author":"EU Alum","year":"2025","unstructured":"Alum EU. 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