肿瘤微环境（TME）的状况与头颈鳞状细胞癌（HNSCC）的发展密切相关，并显着影响免疫治疗的疗效。最近的研究强调了 PNCK 在癌症进展中的关键作用，但其与免疫治疗的关系仍然难以捉摸。我们利用队列和公共数据库的测序数据来评估 PNCK 表达、预后意义和免疫功效预测。体外和体内实验探讨了 PNCK 在 HNSCC 进展中的作用。动物模型评估了 PNCK 敲低联合免疫检查点抑制剂 (ICIs) 的治疗效果和生存益处。单细胞转录组学分析了PNCK对TME的影响，蛋白质组学研究阐明了其机制。PNCK在HNSCC的进展中发挥多方面的关键作用。较低的 PNCK 表达与预后改善、免疫细胞浸润增强以及对 ICI 的反应性增强相关。相反，PNCK 促进小鼠 HNSCC 细胞迁移、侵袭、增殖、集落形成、斑马鱼血管生成和肿瘤生长。此外，靶向 PNCK 增强了对 ICI 的敏感性，并导致 TME 内 T 细胞和 B 细胞比例的显着改变。这些变化归因于 PNCK 磷酸化 ZEB1 的核转录受到抑制，从而限制细胞因子的释放并刺激免疫微环境来调节 TME。抑制 PNCK 可能是治疗 HNSCC 的潜在策略，因为它可以激活免疫反应并抑制 TME。改善 TME，从而增强 HNSCC 患者免疫治疗的功效。© 作者（或其雇主）2024。CC BY-NC 允许重复使用。禁止商业再利用。请参阅权利和权限。英国医学杂志出版。

The landscape of the tumor microenvironment (TME) is intricately linked to the development of head and neck squamous cell carcinoma (HNSCC) and significantly influences immunotherapy efficacy. Recent research has underscored the pivotal role of PNCK in cancer progression, yet its relationship with immunotherapy remains elusive.We leveraged sequencing data from our cohort and public databases to evaluate PNCK expression, prognostic significance, and immune efficacy prediction. In vitro and in vivo experiments explored the role of PNCK in HNSCC progression. Animal models assessed the therapeutic effects and survival benefits of PNCK knockdown combined with immune checkpoint inhibitors (ICIs). Single-cell transcriptomics analyzed the impact of PNCK on the TME, and proteomic studies elucidated the mechanisms.PNCK exerts multifaceted critical roles in the progression of HNSCC. Lower PNCK expression is associated with improved prognosis, enhanced immune cell infiltration, and increased responsiveness to ICIs. Conversely, PNCK promotes HNSCC cell migration, invasion, proliferation, colony formation, zebrafish angiogenesis, and tumor growth in mice. Moreover, targeting PNCK enhances sensitivity to ICIs and leads to significant alterations in the T-cell and B-cell ratios within the TME. These changes are attributed to the inhibition of nuclear transcription of PNCK-phosphorylated ZEB1, which restricts cytokine release and inflames the immune microenvironment to regulate the TME.Inhibition of PNCK may be a potential strategy for treating HNSCC, as it may activate the immune response and improve the TME, thereby enhancing the efficacy of immunotherapy for HNSCC patients.© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.