METTL14 Enhances Anti-Tumor Immunity through m6A-dependent loss of PD-1

N6-methyladenosine (m6A) modifications can impact immune responses by regulating different target genes. Here, we demonstrated that the programmed cell death-1 (PD-1) gene PDCD1 undergoes m6A modification, which subsequently impacts 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.