A METTL3-NFE2L3 axis mediates tumor stemness and progression in lung adenocarcinoma

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 <i>N</i>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.