Genes, fuel, and fate in lung cancer

Abstract Cellular plasticity is a central feature of malignant progression, allowing tumour cells to change identity during tumour evolution, therapeutic adaptation, and metastatic dissemination. This issue is especially acute in lung cancer, where the respiratory epithelium is intrinsically permissive to cell-state change. Genetic lesions, chromatin regulation, and metabolic adaptation are often framed as parallel determinants of lineage plasticity. Emerging evidence instead points to functional coupling across these layers. Oncogenic alterations can weaken lineage fidelity and open alternative trajectories, chromatin regulators can stabilise transitional states and enforce new transcriptional programmes, and metabolic rewiring can supply the biochemical conditions required for these states to emerge and persist. Microenvironmental cues further influence which trajectories are selected and maintained. Here, we discuss the genetic, epigenetic, and metabolic determinants of lineage plasticity in lung cancer, focusing on the points at which they intersect. We propose that plasticity is most usefully understood as a coupled regulatory state, arising from the interaction between oncogenic context, chromatin control, and metabolic support. Defining how these dependencies arise and become functionally coupled within high-plasticity transitional states should help identify points at which lineage switching can be intercepted before alternative lineage programmes are stabilised.