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

Abstract

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.