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Background  Cancer cells selectively promote the translation of oncogenic transcripts to stimulate cancer progression. Although growing evidence has revealed that tRNA modifications and related genes participate in this process, their roles in head and neck squamous cell carcinoma (HNSCC) remain largely uncharacterized. Here, we sought to investigate the function and mechanisms of the transfer RNA (tRNA) N7‐methylguanosine (m 7 G) modification in regulating the occurrence and development of HNSCC.    Methods  Cell lost‐of‐function and gain‐of‐function assays, xenograft models, conditional knockout and knockin mouse models were used to study the physiological functions of tRNA m 7 G modification in HNSCC tumorigenesis. tRNA modification and expression profiling, mRNA translation profiling and rescue assays were performed to uncover the underlying molecular mechanisms. Single‐cell RNA sequencing (scRNA‐seq) was conducted to explore the tumor microenvironment changes.    Results  The tRNA m 7 G methyltransferase complex components Methyltransferase‐like 1 (METTL1)/WD repeat domain 4 (WDR4) were upregulated in HNSCC and associated with a poor prognosis. Functionally, METTL1/WDR4 promoted HNSCC progression and metastasis in cell‐based and transgenic mouse models. Mechanistically, ablation of METTL1 reduced the m 7 G levels of 16 tRNAs, inhibiting the translation of a subset of oncogenic transcripts, including genes related to the phosphatidylinositol‐3‐kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. In addition, chemical modulators of the PI3K/Akt/mTOR signaling pathway reversed the effects of Mettl1 in mouse HNSCC. Furthermore, scRNA‐seq results revealed that Mettl1 knockout in mouse tumor cells altered the immune landscape and cell‐cell interaction between the tumor and stromal compartment.    Conclusions  The tRNA m 7 G methyltransferase METTL1 was found to promote the development and malignancy of HNSCC through regulating global mRNA translation, including the PI3K/AKT/mTOR signaling pathway, and found to alter immune landscape. METTL1 could be a promising treatment target for HNSCC patients.

Aberrant translation regulated by METTL1/WDR4‐mediated tRNA N7‐methylguanosine modification drives head and neck squamous cell carcinoma progression