YTHDF3 suppresses interferon-stimulated gene (ISG)-dependent antitumor immunity and promotes HPV carcinogenesis in cervical cancer

TL;DR

This study shows that YTHDF3 suppresses antiviral immunity and promotes cervical cancer caused by HPV by regulating RNA modifications and immune cell infiltration.

Contribution

The novel finding is that YTHDF3 promotes HPV carcinogenesis by suppressing ISG responses through m6A-dependent regulation of STAT3.

Findings

YTHDF3 suppresses type I ISG responses by stabilizing STAT3 mRNA through m6A modification.

YTHDF3-STAT3 axis represses IRF7 and IFN-α production, weakening antiviral immunity in HPV+ cancer.

Ythdf3−/− mice showed reduced immunosuppressive immune cells and enhanced CD8+ T cell activation in tumors.

Abstract

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 Ythdf3−/− 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, Ythdf3− 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.

Figures