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<p>Hypopharyngeal squamous cell carcinoma (HPSCC), an aggressive head and neck cancer with dismal prognosis, faces persistent chemoresistance to standard TPF (docetaxel, cisplatin, 5-fluorouracil) regimen. However, the immunological mechanisms underlying chemoresistance remain undefined. Here, we perform longitudinal single-cell RNA sequencing (scRNA-seq) profiling of paired pre-/post-TPF HPSCC specimens, mapping immune cell dynamics underlying chemoresistance. Our study identifies ZNF683<sup>+</sup> natural killer (NK) cells as a gatekeeper of chemotherapy efficacy through integrated single-cell transcriptomics, spatial multiplex immunohistochemistry and functional validation. Moreover, pretreatment baseline enrichment of ZNF683<sup>+</sup> NK cells predicts TPF response, while GZMK<sup>+</sup>CD8<sup>+</sup> effector memory T cells function as the predominant immunologic effector to successful TPF intervention. Mechanistically, bioinformatics and in vitro coculture data reveal that ZNF683<sup>+</sup> NK cells directly interact with CD8<sup>+</sup> T cells, and drive an MHC-I-dependent licensing of polyfunctional GZMK<sup>+</sup>CD8<sup>+</sup> effector memory T cells. Collectively, this NK-CD8<sup>+</sup> axis provides a potential predictive biomarker and therapeutic target to overcome chemoresistance in patients with HPSCC.</p>

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ZNF683+ NK cells govern chemotherapy sensitivity in advanced HPSCC via reshaping immune microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • Guo Li,
  • Wenhao Xiao,
  • Haijun Wu,
  • Chao Liu,
  • Liang Gong,
  • Haoyu Zhang,
  • Zhuo Shao,
  • Jing Bai,
  • Xuefeng Xia,
  • Xin Yi,
  • Yunyun Wang,
  • Shanhong Lu,
  • Li She,
  • Juncheng Wang,
  • Gangcai Zhu,
  • Xiaojuan Zhou,
  • Wenmei Wang,
  • Liangfang Shen,
  • Nu Zhang,
  • Xingwei Wang,
  • Donghai Huang,
  • Junwei Hou,
  • Yuanzheng Qiu,
  • Xin Zhang,
  • Mien-Chie Hung,
  • Yong Liu

摘要

Hypopharyngeal squamous cell carcinoma (HPSCC), an aggressive head and neck cancer with dismal prognosis, faces persistent chemoresistance to standard TPF (docetaxel, cisplatin, 5-fluorouracil) regimen. However, the immunological mechanisms underlying chemoresistance remain undefined. Here, we perform longitudinal single-cell RNA sequencing (scRNA-seq) profiling of paired pre-/post-TPF HPSCC specimens, mapping immune cell dynamics underlying chemoresistance. Our study identifies ZNF683+ natural killer (NK) cells as a gatekeeper of chemotherapy efficacy through integrated single-cell transcriptomics, spatial multiplex immunohistochemistry and functional validation. Moreover, pretreatment baseline enrichment of ZNF683+ NK cells predicts TPF response, while GZMK+CD8+ effector memory T cells function as the predominant immunologic effector to successful TPF intervention. Mechanistically, bioinformatics and in vitro coculture data reveal that ZNF683+ NK cells directly interact with CD8+ T cells, and drive an MHC-I-dependent licensing of polyfunctional GZMK+CD8+ effector memory T cells. Collectively, this NK-CD8+ axis provides a potential predictive biomarker and therapeutic target to overcome chemoresistance in patients with HPSCC.