头颈鳞状细胞癌 (HNSCC) 是全球第六大常见癌症类型。近年来，由于口咽部感染人乳头瘤病毒（HPV）而导致的 HNSCC 病例有所增加。鉴于当前 HPV 阳性 HNSCC 护理标准存在显着的治疗相关毒性，迫切需要制定精确的患者分层和治疗策略，以提高患者的生活质量，同时保持良好的生存率。我们之前对顺铂和放射治疗失败的 HPV HNSCC 肿瘤进行了全基因组测序，发现这些肿瘤中 MACROD2 缺失较多。在当前的研究中，我们试图探讨 MACROD2 在 HPV HNSCC 治疗耐药中的机制作用。我们的结果表明，HNSCC 细胞系中 MACROD2 的缺失导致细胞活力和集落形成能力增加。有趣的是，MACROD2 缺失并没有改变顺铂敏感性，而是导致 HPV HNSCC 细胞系的辐射耐受性增加。 RNA测序和免疫荧光显微镜表明，MACROD2耗尽的HPV HNSCC细胞表现出缺氧水平升高和DNA损伤反应改变。综上所述，本研究确立并表征了 MACROD2 在 HPV HNSCC 放射抗性中的作用。需要进一步的工作来验证 MACROD2 作为治疗失败的生物标志物，并了解如何克服已确定的耐药分子机制。版权所有 © 2024 作者。由爱思唯尔有限公司出版。保留所有权利。

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide. In recent years, there has been an increase in the rate of HNSCC cases attributed to the infection of the oropharynx by the human papillomavirus (HPV). Given the significant treatment-related toxicities of the current standard of care for HPV-positive HNSCC, there is an urgent need for the development of precision patient stratification and treatment strategies to improve patients' quality of life while maintaining excellent survival rates. We have previously carried out whole genome sequencing of HPV+ HNSCC tumors that failed concurrent cisplatin and radiation treatment and discovered that MACROD2 deletion is enriched among these tumors. In the current study, we sought to investigate the mechanistic role of MACROD2 in HPV+ HNSCC treatment resistance. Our results indicate that MACROD2 depletion in HNSCC cell lines leads to increased cell viability and colony formation capacity. Interestingly, MACROD2 depletion did not alter cisplatin sensitivity but led to an increase in radiation resistance of HPV+ HNSCC cell lines. RNA sequencing and immunofluorescence microscopy demonstrated that MACROD2-depleted HPV+ HNSCC cells displayed elevated levels of hypoxia and an altered DNA damage response. Taken together, this study establishes and characterizes the role of MACROD2 in HPV+ HNSCC radioresistance. Further work is needed to validate MACROD2 as a biomarker of treatment failure and to understand how to overcome the identified molecular mechanisms of resistance.Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.