人类内源性逆转录病毒（HERV）正在成为宿主基因组调控的关键元件。异常的 HERV 转录与发育和组织特异性衰老和病理过程有关。在这项研究中，我们对食管鳞状细胞癌 (ESCC) 中 HERV 表达情况进行了全面的位点特异性表征。我们证明了患者之间的转录多样性，并在 SCH 队列中鉴定出了 12 种临床相关的 HERV，并在 CAMS 队列中通过实时定量聚合酶链反应 (RT-qPCR) 进行了实验验证。 ESCC 患者被分为三种基于 HERV 的亚型（HERVhigh、HERVmedian 和 HEVlow），具有不同的临床和生物学特征。 HERVhigh 亚型与较差的生存率、CD4 T 细胞浸润增加和代谢活动降低相关，而 HERVlow 亚型的特点是 CD8 T 细胞丰富、代谢活动增加和更好的生存率。基于 HERV 的肿瘤亚型在另外两个外部队列中通过 RNA 测序和 RT-qPCR 得到了进一步的有力验证。我们的研究结果证明了 HERV 对肿瘤亚型和预后的临床意义，提供了对 HERV 功能作用的见解，并为开发 ESCC 的新型生物标志物和治疗靶点提供了宝贵的资源。© 2024 UICC。

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 (HERVhigh, HERVmedian and HERVlow) with distinct clinical and biological characteristics. The HERVhigh subtype was associated with worse survival, increased CD4+ T cells infiltration and decreased metabolic activity, whereas the HERVlow 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.© 2024 UICC.