N6-methyladenosine (m6A) writer METTL5 represses the ferroptosis and antitumor immunity of gastric cancer

Emerging evidence has shown that ferroptosis and antitumor immunity response of T lymphocytes play critical roles in multiple malignancies, including gastric cancer (GC). Here, the present research aims to reveal the function of novel N⁶-methyladenosine (m⁶A) methyltransferase METTL5 on GC immune microenvironment. Clinically, elevated METTL5 was negatively correlated to the prognosis of GC patients. METTL5 high-expression repressed the Fe²⁺ accumulation and ferroptosis to promote the GC immune evasion escaping from activated PBMCs’ killing effect. Mechanistically, upregulation of METTL5 promoted NRF2 mRNA stability, thereby inactivating the ferroptosis and repressing PBMCs’ cells antitumor immunity. One valuable finding is that ferroptosis inhibitor (Ferrostatin-1, Fer-1) could reduce the antitumor immunity of cocultured PBMCs. In other words, the increase of ferroptosis might contribute to the anti-tumor efficacy of immunotherapy. Further study revealed that m⁶A reader IGF2BP1 mediated the stability of NRF2 mRNA via METTL5/m⁶A/NRF2 axis. Collectively, these results demonstrate that METTL5 functions as an oncogene in GC immune microenvironment, and highlights a critical role in T lymphocytes’ antitumor immunity.