Persistent lineage plasticity driving lung cancer development and progression

Abstract Background Lung cancer, a leading cause of cancer death, displays profound histologic and molecular heterogeneity across adenocarcinoma, squamous, and small‐cell types. Clinically, tumours can shift between these states, reflecting lineage plasticity—the reprogramming of differentiated cells to alternate identities. Pre‐existing genomic/epigenomic diversity and microenvironmental cues supply the substrates and pressures for plasticity from disease onset. This review anchors plasticity within normal lung development to clarify how fate programs are co‐opted to drive progression, immune escape, therapy resistance, and invasion. Main text Focusing on the intricate interplay between lineage dysregulation and tumour progression in lung cancer, this review integrates insights from lung tissue development to explore the pivotal molecules and mechanisms driving lineage plasticity, alterations and migration during lung carcinogenesis and progression. Recent research findings on lung cancer lineage plasticity are synthesised, shedding light on the role of transcriptional and epigenetic regulators in disrupting tumour lineages. Particular emphasis is placed on how tumour microenvironmental factors, such as hypoxia, stromal cells and immune cells, reshape tumour cellular profiles by modulating the epigenomic landscape. Furthermore, this review specifically discusses the impact of epidermal growth factor receptor ( EGFR) and KRAS mutations on lung cancer progression and the consequent immune escape mechanisms they engender. Importantly, we highlight that lineage regulation persists throughout tumour development, from the early onset of lung adenocarcinoma (LUAD) to its progression through late‐stage dedifferentiation and metastasis. We evaluate the implications of these factors on treatment resistance in lung cancer and focus on innovative therapeutic strategies targeting lineage plasticity. Conclusions Lineage plasticity spans the entire course of lung cancer, from early tumorigenesis through metastasis to treatment resistance. Lineage transitions that occur during tumour progression arise from specific combinations of genomic and epigenetic alterations and are further shaped by microenvironmental forces such as hypoxia, stromal remodeling, and immune pressure. By summarising current research advancements, we aim to provide new insights for future lung cancer research and to promote the development of more effective therapeutic interventions. Key points Lineage plasticity runs through the entire process of lung cancer progression and drug resistance, and drives early tumorigenesis via lineage imbalance. Certain driver mutations have lineage‐restricted tumorigenic potential, requiring lineage reprogramming for tumor initiation. Lineage transitions in lung cancer require specific genomic and epigenetic alterations. Lineage plasticity insights provide a mechanistic framework linking lung cancer origin, evolution, and therapeutic vulnerabilities.