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

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. In patients with hypopharyngeal squamous cell carcinoma (HPSCC), resistance to the standard-of-care induction chemotherapy often occurs. Here, using longitudinal single-cell transcriptomic profiling of HPSCC samples from patients receiving induction chemotherapy, the authors identify a ZNF683-high natural killer (NK) cell population as a predictor of chemotherapy response.