ZC3H13‐mediated m6A stabilization of CCND1 promotes malignant progression and is associated with poor anti‐PD‐1 response in HNSCC

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.