The transcriptional landscape and clinico‐biological characterization of human endogenous retroviruses in esophageal squamous cell carcinoma

Abstract Human endogenous retroviruses (HERVs) are emerging as critical elements in host genomic regulation. Aberrant HERV transcription has been implicated in developmental and tissue‐specific aging and pathological processes. In this study, we presented a comprehensive locus‐specific characterization of the HERV expression landscape in esophageal squamous cell carcinoma (ESCC). We demonstrated the transcriptional diversity among patients and identified 12 clinically relevant HERVs in the SCH cohort, which were experimentally validated by Real‐Time Quantitative Polymerase Chain Reaction (RT‐qPCR) in the CAMS cohort. ESCC patients were stratified into three HERV‐based subtypes (HERV high , HERV median and HERV low ) with distinct clinical and biological characteristics. The HERV high subtype was associated with worse survival, increased CD4+ T cells infiltration and decreased metabolic activity, whereas the HERV low subtype was characterized by abundant CD8+ T cells, increased metabolic activity, and better survival. The HERV‐based tumor subtyping was further robustly validated by RNA sequencing and RT‐qPCR in two additional external cohorts. Our findings demonstrate the clinical significance of HERVs for tumor subtyping and prognosis, provide insights into the functional role of HERVs and a valuable resource for developing novel biomarkers and therapeutic targets in ESCC.