YTH domain family protein 3 accelerates non-small cell lung cancer immune evasion through targeting CD8 T lymphocytes.

Immune evasion is one of the critical hallmarks of malignant tumors, especially non-small cell lung cancer (NSCLC). Emerging findings have illustrated the roles of N-methyladenosine (mA) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of mA reader YTH domain family protein 3 (YTHDF3) on NSCLC immune evasion. YTHDF3 was found to be highly expressed in NSCLC tissue and act as an independent prognostic factor for overall survival. Functionally, up-regulation of YTHDF3 impaired the CD8 T antitumor activity to deteriorate NSCLC immune evasion, while YTHDF3 silencing recovered the CD8 T antitumor activity to inhibit immune evasion. Besides, YTHDF3 up-regulation reduced the apoptosis of NSCLC cells. Mechanistically, PD-L1 acted as the downstream target for YTHDF3, and YTHDF3 could upregulate the transcription stability of PD-L1 mRNA. Overall, YTHDF3 targeted PD-L1 to promote NSCLC immune evasion partially through escaping effector cell cytotoxicity CD8 T mediated killing and antitumor immunity. In summary, this study provides an essential insight for mA modification on CD8 T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.