Tumour-brain crosstalk restrains cancer immunity via a sensory-sympathetic axis.

Abstract

Body-brain communication has emerged as a key regulator of tissue homeostasis^1-5. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes^6-8. However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour-brain communication influences cancer immunity. Here we identify a tumour-brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment. Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain. Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment. This, in turn, suppresses anti-tumour immunity via β₂ adrenergic signalling 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.