Methyltransferase-Like 3 Inhibition-Activated cGAS/STING Axis Enhances Immunotherapy and Poly(ADP-Ribose) Polymerase...

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)-mediated type I interferon response plays a crucial role in antitumor immunity, yet the regulatory factors involved in this innate immune response remain incompletely understood. Here, we identified methyltransferase-like 3 (METTL3), an RNA N⁶ -methyladenosine methyltransferase, as a key suppressor of the cGAS/STING pathway in lung adenocarcinoma (LUAD) cells. METTL3 was overexpressed in LUAD tissues, and elevated METTL3 expression was associated with decreased CD8⁺ T-cell infiltration and poor clinical outcomes. Mechanistically, METTL3 deficiency promoted nuclear DNA leakage into the cytoplasm, thereby activating the cGAS pathway and enhancing antitumor immunity. Specifically, METTL3 knockdown decreased the efficiency of homologous recombination repair by down-regulating MutS homolog 5, leading to cytosolic DNA accumulation. On the other hand, N⁶ -methyladenosine methylation of cGAS messenger RNA destabilized the transcript and suppressed its protein expression. Functionally, METTL3 knockdown sensitized LUAD cells to poly(ADP-ribose) polymerase inhibitors. In vivo and clinical data confirmed the beneficial effects of METTL3-inhibition-induced activation of the cGAS/STING axis on tumor growth and LUAD progression. Collectively, our findings reveal that METTL3 inhibition activates cGAS/STING-mediated antitumor immunity by inducing cytosolic DNA accumulation and cGAS up-regulation, thereby modulating poly(ADP-ribose) polymerase inhibitor response and cancer progression in LUAD.