A vagal sensory-to-sympathetic axis restrains anti-tumor immunity

Body-brain communication has emerged as a key regulator of tissue homeostasis. Solid tumours are innervated by different branches of the peripheral nervous system, and increased tumour innervation is associated with poor cancer outcomes. However, it remains unexplored how the brain senses and responds to tumours in peripheral organs, and how tumour-brain communication influences cancer immunity. Here, we identify a previously unrecognized tumour-brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment (TME). Combining genetically engineered mouse models with neural tracing, calcium imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces increased innervation, activation and transcriptional alterations in vagal sensory neurons (VSNs), a major interoceptive system connecting visceral organs to the brain. Mechanistically, Npy2r+ vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the TME. This, in turn, suppresses anti-tumour immunity via β2-adrenergic signaling in alveolar macrophages. Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer. Collectively, these results reveal a bidirectional tumour-brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour-brain circuit may provide new treatments for visceral organ cancers.