Head and neck squamous cell carcinoma (HNSCC) is one of the deadliest human cancers, with the overall 5-year survival rate stagnating in recent decades due to the lack of innovative treatment approaches. Apart from the recently Food and Drug Administration–approved epidermal growth factor receptor inhibitor and immune checkpoint inhibitor, alternative therapeutic strategies that target epigenetic abnormalities, an emerging cancer hallmark, remain to be fully explored. A pathological epigenetic landscape, characterized by widespread reprogramming of chromatin modifications such as DNA methylation and histone modifications, which drives transcription deregulation and genome reorganization, has been extensively documented in numerous cancers, including HNSCC. Growing evidence indicates that these frequent epigenomic alterations play pivotal roles in regulating malignant transformation, promoting metastasis and invasion, and reshaping the tumor microenvironment. Furthermore, these epigenetic changes also present unique vulnerabilities that open new avenues for identifying novel prognostic biomarkers and developing targeted antitumor therapies. In this review, we summarize recent discoveries of epigenetic dysregulations in HNSCC, with a focus on deregulated chromatin modifications, which include aberrant DNA methylation, oncohistone H3 lysine 36 to methionine (H3K36M) mutation, as well as recurrent mutations or altered expression of chromatin-modifying enzymes such as NSD1, EZH2, and KMT2C/D. Importantly, we discuss the various molecular mechanisms underlying the contributions of these epigenetic alterations to HNSCC development, particularly their involvement in deregulated cell proliferation and cell death, metabolic reprogramming, tumor immune evasion, and phenotypic plasticity. Finally, we conclude by highlighting the translational and clinical implications of targeting the epigenetic machinery, which offers promising prospects for overcoming resistance to conventional radiotherapy/chemotherapy and enhancing the response to immunotherapy in HNSCC.

中文翻译：

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靶向头颈部鳞状细胞癌的表观遗传失调


头颈部鳞状细胞癌 （HNSCC） 是最致命的人类癌症之一，由于缺乏创新的治疗方法，近几十年来总体 5 年生存率停滞不前。除了最近获得美国食品药品监督管理局批准的表皮生长因子受体抑制剂和免疫检查点抑制剂外，针对表观遗传异常（一种新兴的癌症标志）的替代治疗策略仍有待充分探索。病理性表观遗传景观，其特征是染色质修饰（如 DNA 甲基化和组蛋白修饰）的广泛重编程，这推动了转录失调和基因组重组，已在包括 HNSCC 在内的许多癌症中得到广泛记录。越来越多的证据表明，这些频繁的表观基因组改变在调节恶性转化、促进转移和侵袭以及重塑肿瘤微环境方面起着关键作用。此外，这些表观遗传变化还呈现出独特的脆弱性，为识别新的预后生物标志物和开发靶向抗肿瘤疗法开辟了新的途径。在这篇综述中，我们总结了 HNSCC 表观遗传失调的最新发现，重点是染色质修饰失调，包括异常的 DNA 甲基化、癌组蛋白 H3 赖氨酸 36 到蛋氨酸 （H3K36M） 突变，以及 NSD1 、 EZH2 和 KMT2C/D 等染色质修饰酶的复发突变或表达改变。 重要的是，我们讨论了这些表观遗传改变对 HNSCC 发育贡献的各种分子机制，特别是它们参与失调的细胞增殖和细胞死亡、代谢重编程、肿瘤免疫逃避和表型可塑性。最后，我们总结强调了靶向表观遗传机制的转化和临床意义，这为克服对常规放疗/化疗的耐药性和增强 HNSCC 对免疫治疗的反应提供了有希望的前景。