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OBJECTIVES Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer. Chemotherapy has been recognized as an optional combination treatment, which enhance the overall survival of OSCC patients. However, the majority of patients would suffer therapeutic resistance, which led to the treatment failure and poor prognosis. MATERIALS AND METHODS To explore the mechanism of chemoresistance in OSCC, we first constructed two chemoresistant cell lines using Cal27 and HSC4. Then MeRIP sequencing together with bioinformatics analysis and a seris of in vitro experiments were used to assess the possible regulation manner of RNA methylation on OSCC chemoresistance. Finally, xenograft models were constructed to confirm the relationship among OSCC chemoresistance. RESULTS METTL3/METTL14 up-regulation could enhance OSCC chemoresistance. CEBPA-DT overexpression could regulate METTL3/METTL14 expression and further activate downstream BHLHB9. CEBPA-DT overexpression could inhibit the activity of IL-17 signaling, resulting in the homeostasis breakdown of immune infiltration and cytokine release. CEBPA-DT overexpression could significantly enhance chemoresistance through METTL3/METTL14/BHLHB9 in vivo, which accelerated the tumor growth. CONCLUSIONS Our results suggest that CEBPA-DT might regulate OSCC chemoresistance through BHLHB9 gene manipulated by METTL3/METTL14 as well as through IL-17 signaling inhibition, which may contribute to the assessment of potential therapeutic targets in OSCC chemoresistance.