Mitochondrial metabolic-transcriptional axis drives adaptive drug tolerance across major lung cancer subtypes.

Mitochondrial dysfunction and genetic-epigenetic cascades drive drug-tolerant states across lung cancer subtypes.

• Why it matters: Understanding reversible tumor phenotypic plasticity is crucial because traditional resistance mechanisms do not fully explain long-term treatment failure in lung cancer patients, highlighting the need for new therapeutic targets.
• What they did: The review synthesizes preclinical and translational data on mitochondrial metabolic rewiring—including altered OXPHOS, TCA metabolites, ROS imbalance, and mitochondrial quality control—in LUAD, LUSC, and SCLC, focusing on how these processes induce drug-tolerant persister states and lineage plasticity.
• The result: Findings suggest mitochondrial-targeted interventions and multi-omics profiling could improve resistance prediction and enable personalized combination therapies to reverse therapeutic failure in lung cancer.