<p>Interferon-stimulated genes (ISGs) serve as evolutionarily conserved mediators of antiviral defense and tumor surveillance. Emerging evidence underscores the non-oncogenic addiction of high-risk human papillomavirus (hrHPV) E6/E7 oncoproteins in maintaining malignant phenotypes and cervical carcinogenesis. Here, we leveraged CRISPR/Cas9-engineered YTHDF3-knockout (YTHDF3^−/−) SiHa cells and <i>Ythdf3</i>^{<i>−/</i>−} mice to dissect the molecular arbiters governing m⁶A-dependent RNA regulation in HPV-driven carcinogenesis. To further elucidate the role of YTHDF3 in HPV-induced immunosuppressive tumor microenvironment (ITME) formation, we demonstrated that YTHDF3, an m⁶A RNA reader, suppresses type I ISGs responses. Notably, elevated m⁶A modification and YTHDF3 protein levels were observed in HPV⁺ CCa tissues. Mechanistically, YTHDF3 bound to the m⁶A methylation site of STAT3 mRNA, enhancing its stability and transcription efficiency. This YTHDF3-STAT3 axis repressed ISG (e.g., IRF7) transcription and IFN-α production, thereby compromising antiviral immunity and facilitating HPV E6/E7 persistence. Correspondingly, <i>Ythdf3</i>^<i>−</i> mice bearing TC-1 xenografts exhibited a significant reduction in immunosuppressive immune cell infiltration, including Tregs, M2 macrophages, and MDSCs, accompanied by enhanced CD8⁺ T cell activation. Collectively, our findings unveiled that YTHDF3-mediated upregulation of STAT3 suppresses the type I ISG expression, thus promoting HPV carcinogenesis and establishing an ITME. Taken together, our results suggest that targeting the YTHDF3/STAT3/IRF7 axis could be a promising therapeutic strategy against HPV-associated malignancies.</p><p></p>