GLUT6-facilitated noncanonical glucose metabolic rewiring enables resistance to targeted cancer therapy.

Targeting glucose metabolism has long been pursued as an anticancer strategy, yet its clinical translation remains challenging. Achieving therapeutic selectivity requires identifying actionable metabolic distinctions between different malignant traits. Here, we uncover a noncanonical, lactate-independent glucose metabolic pathway facilitated by the glucose transporter 6 (GLUT6), which confers targeted therapy resistance in lung cancer. Downstream, GLUT6 promotes glucose influx and diversion toward methylglyoxal production, leading to kelch-like ECH-associated protein 1 (KEAP1) dimerization and nuclear factor erythroid 2-related factor 2 (NRF2) pathway activation, driving resistance. Upstream, GLUT6 expression is transcriptionally upregulated by therapy-induced MYC associated zinc finger protein (MAZ) activation. Targeting GLUT6 prevents and overcomes EGFR and KRAS inhibitors resistance. Moreover, the MAZ-GLUT6-NRF2 axis correlates with clinical treatment response and relapse. The preferential reliance on GLUT6-a noncanonical transporter with minimal systemic homeostasis perturbation-highlights its promise as a target for overcoming resistance and revitalizing glucose metabolism-based anticancer strategies.