Zhao Xuri, Zhu Yaping, He Youya, Gu Weiyan, Zhou Qi, Jin Bei, Chen Shenguo, Lin Haisheng
Department of Stomatology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Taizhou, Zhejiang, China.
Front Immunol. 2025 May 14;16:1597202. doi: 10.3389/fimmu.2025.1597202. eCollection 2025.
Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by a complex tumor microenvironment (TME) that plays a pivotal role in tumor initiation, progression, and immune evasion. Recent advancements have highlighted the intricate interplay between immune cell infiltration patterns, immune checkpoint dysregulation, and metabolic reprogramming in driving HNSCC immune escape. Despite these insights, significant challenges remain, including the incomplete understanding of specific immune evasion pathways and the lack of personalized therapeutic strategies. To address these gaps, this review introduces a novel "Trinity" regulatory network of immune evasion in HNSCC, encompassing: (1) metabolic reprogramming-mediated immune checkpoint modulation, (2) stromal cell-driven immune dysfunction, and (3) epigenetic remodeling fostering immune tolerance. This framework provides a theoretical foundation for the development of multi-targeted combination therapies and offers innovative strategies to overcome immune evasion. Additionally, this review systematically synthesizes the current understanding of the relationship between the HNSCC microenvironment and immune escape, with a focus on emerging immunotherapeutic approaches such as PD-1/PD-L1 inhibitors and CAR-T cell therapy. Leveraging cutting-edge single-cell sequencing and spatial transcriptomics, we elucidate the spatiotemporal heterogeneity of the HNSCC immune landscape and propose a new paradigm of "lineage plasticity-driven immune adaptation." These insights not only advance our understanding of HNSCC biology but also pave the way for the development of precision immunotherapies aimed at improving patient survival and quality of life. By integrating multidisciplinary perspectives, this work underscores the importance of targeting the TME to achieve durable clinical responses and overcome immunotherapy resistance in HNSCC.
头颈部鳞状细胞癌（HNSCC）是一种侵袭性很强的恶性肿瘤，其特征是具有复杂的肿瘤微环境（TME），该微环境在肿瘤的起始、进展和免疫逃逸中起关键作用。最近的进展突出了免疫细胞浸润模式、免疫检查点失调和代谢重编程之间在驱动HNSCC免疫逃逸方面的复杂相互作用。尽管有这些见解，但仍存在重大挑战，包括对特定免疫逃逸途径的理解不完整以及缺乏个性化治疗策略。为了填补这些空白，本综述介绍了一种新颖的HNSCC免疫逃逸“三位一体”调控网络，包括：（1）代谢重编程介导的免疫检查点调节，（2）基质细胞驱动的免疫功能障碍，以及（3）促进免疫耐受的表观遗传重塑。该框架为多靶点联合治疗的开发提供了理论基础，并提供了克服免疫逃逸的创新策略。此外，本综述系统地综合了目前对HNSCC微环境与免疫逃逸之间关系的理解，重点关注新兴的免疫治疗方法，如PD-1/PD-L1抑制剂和CAR-T细胞疗法。利用前沿的单细胞测序和空间转录组学，我们阐明了HNSCC免疫格局的时空异质性，并提出了一种“谱系可塑性驱动的免疫适应”新范式。这些见解不仅推进了我们对HNSCC生物学的理解，也为开发旨在提高患者生存率和生活质量的精准免疫疗法铺平了道路。通过整合多学科观点，这项工作强调了针对TME以实现持久临床反应并克服HNSCC免疫治疗耐药性的重要性。
