METTL14/IGF2BP2-mediated m6A modification of PD-L1 promotes proliferation, metastasis, and immune escape in high-grade gliomas

N6-methyladenosine (m6A) RNA modification is involved in regulating the malignant progression and immune escape of glioblastoma multiforme (GBM). This study investigated the role of methyltransferase-like protein 14 (METTL14), the central component of the m6A methylated transferase complex, in GBM progression and immune escape. METTL14 and programmed death ligand 1 (PD-L1) levels were analyzed by qRT-PCR and Western blot in human GBM samples. Effects of METTL14 knockdown on GBM tumorigenesis were investigated in mouse tumor xenografts. GBM cell proliferation and metastasis were examined by colony formation assay and transwell assay; immune escape was assessed by detecting cytotoxicity, immune-related markers, and exhaustion markers. The interaction between PD-L1 and METTL14 or the m6A reader IGF2BP2 was confirmed by MeRIP assay and RIP assay. METTL14 was upregulated in GBM tissues and cells and its knockdown reduced GBM tumor growth in the xenografts. Downregulation of METTL14 could suppress GBM cell proliferation, metastasis, and immune escape. METTL14 stabilized PD-L1 mRNA; this modification could be recognized by IGF2BP2. Moreover, PD-L1 overexpression eliminated the inhibitory effect of METTL14 knockdown on GBM cell proliferation, metastasis, and immune escape. In conclusion, METTL14-mediated m6A modification of PD-L1 contributed to GBM cell proliferation, metastasis, and immune escape in an IGF2BP2-dependent manner.