The neural stem cell‑NSCLC axis: Molecular drivers, microenvironment crosstalk and emerging therapies (Review)

Non‑small cell lung cancer (NSCLC), as the main type of lung cancer, is characterized by high heterogeneity and a complex tumor microenvironment (TME), which are key factors contributing to therapeutic resistance, recurrence and metastasis. In recent years, the interaction between neural stem cells (NSCs) and NSCLC, known as the ‘NSC‑NSCLC axis’, has gradually become a research hotspot at the intersection of tumor biology and cancer neuroscience. The present review summarizes the extensive overlap between NSCs and NSCLC stem cells in terms of molecular markers and signaling pathways, and discusses the possible mechanisms through which NSCLC cells ‘hijack’ NSC programs to enhance stemness, therapeutic resistance and metastatic potential. The present review further discusses how the TME actively recruits NSCs and drives their functional reprogramming, thereby promoting tumor progression through the paracrine secretion of neurotrophic factors, the induction of angiogenesis, remodeling of the immune microenvironment and the formation of synapse‑like connections. In addition, the regulatory networks of neurotransmitters, neurotrophic factors and neuropeptides in NSCLC are reviewed, with particular emphasis on evaluating the potential and challenges of emerging therapies targeting neurotransmitter receptors, perineural invasion, neuroendocrine differentiation and brain metastasis. Unlike previous reviews that focused predominantly on a single mechanism or flux, the present review adopts an integrated perspective of the ‘neural stem cell‑non‑small cell lung cancer axis’ to link three tiers: Molecular hijacking, microenvironment remodeling and clinical translation. The present review further highlights translational research priorities, including targeting neurotransmitter receptors, perineural invasion, neuroendocrine transformation and brain metastasis. Additionally, it is proposed that single‑cell and spatial omics are poised to advance this field from phenomenological description toward precise subtyping, providing a novel therapeutic strategy for NSCLC shifting from ‘tumor eradication’ to ‘reprogramming the tumor microecology’.