Neural regulation in lung cancer: from mechanisms to new therapeutic perspectives

Lung cancer remains a leading cause of cancer-related deaths worldwide. Despite advances in targeted therapy and immunotherapy, treatment outcomes are often constrained by tumor heterogeneity and the complex tumor microenvironment. Recent studies highlight the critical role of the nervous system in lung cancer pathogenesis through bidirectional interactions between the central/peripheral nervous system and cancer cells. This review systematically explores how psychological stress, sleep disorders, and smoking influence the initiation and progression of lung cancer via neuroendocrine-immune networks. We further detail the dual roles of key neurotransmitters-including catecholamines, GABA, serotonin, dopamine, glutamate, histamine, and acetylcholine-in regulating tumor proliferation, epithelial-mesenchymal transition, angiogenesis, and immune evasion, with an emphasis on their context-dependent and receptor subtype-specific effects. Emerging evidence indicates that neurotransmitters remodel the tumor microenvironment by modulating immune cell function and receptor-mediated signaling pathways. We also discuss the therapeutic potential of neuromodulatory agents, particularly β-blockers and neurotransmitter receptor-targeted drugs, and their possible synergistic effects with conventional therapies, while critically distinguishing between strategies supported by clinical evidence and those remaining at the preclinical stage. Challenges persist, including neurotransmitter concentration gradients, receptor subtype specificity, and limitations of preclinical models. The convergence of neuroscience and oncology offers promising avenues for innovative lung cancer therapies, underscoring the necessity for interdisciplinary collaboration to translate these discoveries into clinical practice.