Body–brain communication has emerged as a key regulator of tissue homeostasis1,2,3,4,5. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes6,7,8. 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.
身体与大脑之间的通讯已成为组织稳态的关键调节因子1,2,3,4,5。实体肿瘤受外周神经系统不同分支的神经支配，且肿瘤神经支配增加与癌症不良预后相关6,7,8。然而，大脑如何感知并响应外周器官中的肿瘤，以及肿瘤-大脑通讯如何影响癌症免疫，目前尚不清楚。在此，我们揭示了一条通过建立免疫抑制性肿瘤微环境来促进肿瘤发生的肿瘤-大脑轴。结合基因工程小鼠模型与神经示踪、组织成像和单细胞转录组学，我们证明肺腺癌诱导迷走感觉神经元（连接内脏器官与大脑的主要内感系统）的神经支配和功能激活。机制上，表达Npy2r的迷走感觉神经将肺肿瘤信号传递至脑干核团，驱动肿瘤微环境中交感传出活性增强，进而通过肺泡巨噬细胞中的β2肾上腺素能信号抑制抗肿瘤免疫。通过遗传、药理或化学遗传学手段阻断这一感觉-交感通路，可增强抗肿瘤免疫反应，显著抑制肺肿瘤生长。综上所述，这些结果揭示了一种涉及迷走感觉传入和交感传出的双向肿瘤-大脑通讯，二者协同调节抗癌免疫；靶向这一肿瘤-大脑环路或可为内脏器官癌症提供新疗法。
Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis
肿瘤(癌症)患者之家