Tumor–Brain Communication Mediates Immune Escape of Lung Cancer

Tumor innervation is associated with poor prognosis across cancers, yet how these connections influence cancer progression remains unclear. In this study, Wei, Yu, and colleagues studied neuron-mediated communication between tumors in peripheral organs and the brain using genetically engineered mouse models of lung adenocarcinoma. 3D tissue labeling and imaging analyses revealed significant vagal sensory nerve (VSN) innervation of both autochthonous and orthotopic lung tumors, but not healthy alveoli. Exposure of VSNs to tumor-conditioned media, but not media from healthy cells, induced neurite outgrowth. Compared to healthy lung–innervating VSNs, tumor-innervating VSNs displayed upregulation of genes involved in sensory nerve functions, nerve growth, and immune responses, indicating that tumor-secreted factors promote innervation and VSN reprogramming. Ablation of NPY2R/TRPV1 VSNs, but not P2RY1 VSNs, inhibited lung tumor growth in a manner dependent on CD4+ and CD8+ effector T cell responses. Furthermore, VSN ablation led to reduced ARG1 expression and increased MHC-II expression on alveolar macrophages, indicating that NPY2R/TRPV1 neurons support the immunosuppressive polarization of alveolar macrophages. Tumor-innervating NPY2R/TRPV1 VSNs were found to communicate with rostral ventrolateral medulla (RVLM) neurons in the brainstem, selectively activating the sympathetic efferent pathway and increasing noradrenaline concentrations in the lung. Local activation of the sympathetic pathway via inhalation of salbutamol, a β2-adrenergic receptor (ADRB2) agonist, increased lung tumor growth, while ADRB2 depletion from the hematopoietic compartment restored the antitumor effector functions of alveolar macrophages and CD4+ and CD8+ T cells and reduced lung tumor growth. Finally, noradrenaline treatment increased the immunosuppressive polarization of isolated alveolar macrophages in an ADRB2-dependent manner, while treatment did not alter the cytotoxicity of isolated CD8+ T cells. Altogether, this study identifies a novel tumor–brain axis that suppresses antitumor immunity and may be targeted to inhibit lung cancer progression and improve patient outcomes.Wei HK, Yu CD, Hu B, Zeng X, Ichise H, Li L, et al. Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis. Nature 2026 Feb 4 [Epub ahead of print].Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.