Methylation of DPP9 regulates immune surveillance in non-small cell lung cancer by promoting macrophage ferroptosis via WWP2 ubiquitination.

Lung cancer is one of the most common malignancies worldwide, with approximately 2.2 million new cases diagnosed annually. About 75% of patients die within five years of diagnosis. Non-small cell lung cancer (NSCLC) is the predominant histological subtype. In the present study, we aimed to comprehensively elucidate the effects of dipeptidyl peptidase 9 (DPP9) in model of NSCLC. DPP9 mRNA expression and protein expression were up-regulation in patients with NSCLC. Then, Sh-DPP9 reduced cancer growth in mice model of NSCLC. N6-methyladenosine (m6A) increased DPP9 RNA stability of macrophage in NSCLC. DPP9 reduced immune surveillance and promoted Macrophage ferroptosis in vitro model. Meanwhile, si-DPP9 increased immune surveillance and reduced Macrophage ferroptosis in vitro model. DPP9 increased reactive oxygen species (ROS) ROS-mitochondrial oxidation and mitochondrial damage in Macrophage of vitro model. DPP9 reduced activating transcription factor 4 (ATF4) protein expression to promote WW domain-containing E3 ubiquitin protein ligase 2 (WWP2) ubiquitination in Macrophage. ATF4 inhibitor or WWP2 inhibitor reduced the effects of si-DPP9 in ferroptosis of macrophage in model of NSCLC. In conclusion, DPP9 up-regulation promotes WWP2 ubiquitination, thereby inhibiting the WWP2/ATF4 signaling pathway and enhancing macrophage ferroptosis, which leads to reduced immune surveillance and promotes tumor progression in NSCLC.