A METTL3-NFE2L3 axis mediates tumor stemness and progression in lung adenocarcinoma
Yue Zhao, Lei Zhang, Lang Xia, E Haoran, Tao Wang, Huinan Lu, Hezhong Chen, Yunlang She, Hao Tang, Junqi Wu, Deping Zhao, Chang Chen
Abstract
The progression of lung adenocarcinoma is primarily driven by cancer stem cells (CSCs), which have self-renewal capabilities and confer resistance to therapies, including neoadjuvant treatments combining chemotherapy and immune checkpoint inhibitors. In this study, we identified that OV6 + tumor cells exhibit stem-like characteristics and are notably enriched in patients with non–major pathological response, closely associated with resistance to combination therapies. Hypoxia and HIF1α were found to drive the formation of OV6 + CSCs. METTL3, a methyltransferase, was revealed as a critical regulator of OV6 + CSCs by stabilizing NFE2L3 messenger RNA via an N 6 -methyladenosine–dependent manner, thereby up-regulating NFE2L3 and activating the intrinsic WNT signaling pathway essential for maintaining stemness. OV6 + tumor cells promoted M2 macrophage infiltration and the formation of an immunosuppressive tumor microenvironment (TME). Targeting METTL3 effectively eliminated OV6 + CSCs and suppressed tumor progression. Moreover, the combination of STM2457 with cisplatin overcame chemoresistance, remodeled the TME, and provided promising insights for enhancing the efficacy of neoadjuvant combination therapies.