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Abstract 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 6 -methyladenosine (m 6 A) on NSCLC immune evasion. Here, this study investigated the function and underlying mechanism of m 6 A 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 m 6 A modification on CD8 + T cell-mediated antitumor immunity in NSCLC, which might inspire an innovation for lung cancer tumor immunotherapy.
Luo et al. (Thu,) studied this question.