Abstract Background Resistance to immune checkpoint blockade substantially limits its clinical efficacy in head and neck squamous cell carcinoma(HNSCC). ZC3H13 is a component of the N6‐methyladenosine writer complex, but its roles in HNSCC progression and response to anti‐programmed cell death protein 1(anti‐PD‐1) therapy remain unclear. Methods The expression and clinical relevance of ZC3H13 were evaluated using clinical cohorts and publicly available transcriptomic datasets. Gain‐ and loss‐of‐function experiments were performed to determine the effects of ZC3H13 on the malignant phenotypes of HNSCC cells. An epithelial‐specific ZC3H13 conditional knockout mouse model of 4‐nitroquinoline‐1‐oxide‐induced oral tumorigenesis was used to assess tumor development and responsiveness to anti‐PD‐1 therapy. N6‐methyladenosine modification, RNA stability and functional rescue assays were conducted to investigate the underlying molecular mechanism. Results ZC3H13 was upregulated in HNSCC and was associated with poor prognosis and a limited response to anti‐PD‐1 treatment. ZC3H13 promoted the proliferation and invasion of HNSCC cells, whereas epithelial‐specific ablation of ZC3H13 suppressed oral tumorigenesis and enhanced the therapeutic efficacy of anti‐PD‐1 treatment. Mechanistically, ZC3H13 regulated the N6‐methyladenosine modification of cyclin D1(CCND1) mRNA and promoted its IGF2BP1‐dependent stabilization, thereby contributing to malignant tumor phenotypes and alterations in immunosuppressvie features. Conclusions The ZC3H13/IGF2BP1/CCND1 regulatory axis contributes to HNSCC progression and resistance to anti‐PD‐1 therapy. These findings identify ZC3H13 as a potential therapeutic target for improving the efficacy of anti‐PD‐1 treatment in HNSCC.
Wen-Qing Chen, Yun Li, Shuang Chen et al.· Clinical and Translational M...· 0 citations
BACKGROUND
Hypopharyngeal squamous cell carcinoma (HPSCC) is a rare, highly aggressive malignancy, with recurrence playing a pivotal role in treatment failure and cancer-related mortality. The tumor microenvironment (TME) characteristics and molecular mechanisms driving recurrence in HPSCC remain poorly defined.
MATERIALS AND METHODS
Primary HPSCC (P-HPSCC) samples (n = 6) and recurrent HPSCC (R-HPSCC) samples (n = 3) were analyzed. Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics were employed to dissect the cellular composition and molecular characteristics of the TME. Key regulatory networks were identified through gene expression analysis, pathway enrichment, and intercellular communication profiling. Functional validation experiments were performed to confirm the biological relevance of the pathways identified.
RESULTS
ScRNA-seq analysis revealed that malignant epithelial cells (maEpCs) in recurrent tumors exhibited increased stemness, epithelial-mesenchymal transition (EMT), and immune evasion programs. Mechanistically, IGF2BP2 was selectively upregulated in R-HPSCC and functioned as an m6A reader to stabilize SMAD3 mRNA, thereby activating transforming growth factor beta (TGF-β) signaling and facilitating malignant progression. Integrated spatial transcriptomics and functional assays demonstrated that cancer-associated fibroblasts in recurrent tumors promote progression via FN1-mediated signaling. Concurrently, the recurrent TME underwent myeloid remodeling toward an immunosuppressive state, characterized by increased infiltration of SPP1+ tumor-associated macrophages and further enrichment of LAMP3+ dendritic cells with impaired antigen-presenting capacity, alongside aggravated CD8+ T-cell exhaustion, marked by upregulation of CTLA4 as a potential immune escape driver.
CONCLUSIONS
This study identifies recurrence-associated cellular and molecular features in HPSCC. Recurrent tumors exhibited maEpC reprogramming via IGF2BP2-mediated activation of TGF-β signaling, coupled with FN1-dependent stromal activation and immune evasion marked by myeloid immunosuppressive remodeling and CD8+ T-cell exhaustion, characterized by CTLA4 upregulation. Collectively, these findings reveal a pro-recurrent TME and suggest potential therapeutic targets in R-HPSCC.
Z. Cai, Jinhong Zhang, Yaodong Ding et al.· Cellular & Molecular Biology...· 0 citations
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