Neural state as a determinant of tumor immunity in lung cancer

Immune checkpoint blockade has reshaped lung cancer therapy, yet durable benefit remains confined to a minority of patients, and resistance often emerges even in initially responsive disease. An increasingly coherent explanation is that neural state-encoded through hierarchical neuroimmune interactions-can profoundly recalibrate anti-tumor immunity and influence treatment responsiveness. In this Review, we synthesize evidence across three integrated levels of neuro-immune regulation in lung cancer. First, lung tumors engage in local neural-immune-tumor interactions, including synapse-like coupling, neuronal mimicry, perineural niches shaped by injury signaling, tumor-induced neurogenesis and neuroendocrine transitions driven by therapy. These local interfaces concentrate catecholaminergic, cholinergic and sensory neuropeptide signaling within spatial microdomains, repeatedly targeting immune bottlenecks. Second, tumor-initiated peripheral-to-central neural circuits link vagal tumor sensing to brainstem autonomic integration, creating a feedback loop that reshapes peripheral immune status. Third, at the systemic level, psychological stress and circadian disruptions impose neuroendocrine constraints through the hypothalamic-pituitary-adrenal axis and sympathetic nervous system, further amplifying immune heterogeneity and clinical variability. By framing "neural state" as a measurable and actionable clinical variable, this unified three-layered neural-immune model clarifies opportunities for patient stratification, mechanism-informed combinations, and neuromodulatory interventions to optimize immunotherapy efficacy in lung cancer.