METTL14 Enhances Antitumor Immunity through m6A-Dependent Loss of PD-1

N 6-methyladenosine (m6A) modifications can affect immune responses by regulating different target genes. In this study, we demonstrated that the PD-1 gene PDCD1 undergoes m6A modification, which subsequently affects T-cell function. METTL14 mediated PDCD1 downregulation in T cells by promoting m6A-dependent destabilization of PDCD1 mRNA, a process mediated by YTHDF1/2/3. Heterozygous METTL14 deficiency impaired the activation of CD8+ T cells and increased tumor growth by elevating PD-1 levels. Clinically, METTL14 was negatively associated with PDCD1 levels across various cancer types and with resistance to PD-1-targeted immunotherapy. Moreover, WD6305, which degrades the METTL3-METTL14 complex, cooperated with anti-PD-1 therapy to suppress tumor growth in mice. Collectively, these findings reveal an immunoregulatory axis involving m6A modification of PDCD1 and highlight potential therapeutic strategies to enhance the efficacy of tumor immunotherapy. SIGNIFICANCE: Loss of METTL14 elevates PD-1 expression by impeding PDCD1 degradation induced by m6A modification and mediated by YTHDF1/2/3, thereby compromising antitumor immunity and providing a potential avenue for improving immunotherapy.