内源性逆转录病毒和对免疫检查点抑制剂的反应：机制、临床证据和治疗意义
Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications.
摘要(中文译文)
内源性逆转录病毒（ERVs）是远古逆转录病毒整合后经表观遗传沉默的残留序列，约占人类基因组的8%。在癌症中，DNA低甲基化和染色质重塑——无论是自发发生还是由表观遗传治疗诱导——均可解除ERV位点的抑制，导致大量ERV来源的双链RNA（dsRNA）产生，并在某些情况下产生具有免疫原性的ERV蛋白。蓄积的dsRNA主要由MDA5/RIG-I和TLR3识别，激活MAVS/TRIF信号通路，进而诱导IRF3/7和NF-κB依赖的I型干扰素及干扰素刺激基因。这种病毒模拟效应可增强抗原加工和MHC-I提呈，通过CXCL9/10/11招募CXCR3+效应淋巴细胞，促进树突状细胞活化，减少免疫抑制性细胞群体，并可将免疫"冷"肿瘤转化为免疫活跃状态，同时增加PD-L1表达。来自回顾性队列和早期前瞻性研究的临床证据支持ERV特征可作为免疫检查点抑制剂（ICI）应答的生物标志物，且往往独立于PD-L1或肿瘤突变负荷，并有助于基于ERV的分层。诱导ERV或靶向ERV抗原的治疗策略可能使肿瘤对ICI敏感，但检测方法标准化、前瞻性验证和长期安全性仍是关键挑战。
Abstract
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.
如何引用
AMA
Fanyuan Wu, Quezhu Danzeng, Runxi Wu, Yi Shen, Guang Shi. Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1835325.
APA
Fanyuan Wu, Quezhu Danzeng, Runxi Wu, Yi Shen, Guang Shi (2026). Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1835325
GB/T 7714
Fanyuan Wu, Quezhu Danzeng, Runxi Wu, Yi Shen, Guang Shi. Endogenous retroviruses and response to immune checkpoint inhibitors: mechanisms, clinical evidence, and therapeutic implications.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1835325.
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