Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer.
Journal
Cell
ISSN
1097-4172
Date Issued
2026-05-19
Author(s)
Ho, Ya-Hsuan
Bregni, Giacomo
Stazi, Marco
Peinado, Paola
Chen, Pei-Hsing
Ballabio, Claudio
Boulat, Victoire
Vadera, Shree
Guan, Yilin
Liu, Zhikai
Alonso de la Vega, Alicia
Wang, Li
Veiga-Fernandes, Henrique
Downward, Julian
Kopanitsa, Maksym V
Kassiotis, George
Tsantoulas, Christoforos
Schappe, Michael S
Margineanu, Michael-Bogdan
Calado, Dinis Pedro
Chiu, Isaac M
Swanton, Charles
Li, Leanne
Abstract
Sensory innervation regulates lung physiology and pathology, but its role in lung cancer is poorly understood. We show that lung adenocarcinoma (LUAD) progression locally amplifies nociceptive sensory innervation and activation, which drives the release of a major sensory neuropeptide, calcitonin gene-related peptide (CGRP). CGRP acts on a subset of macrophages, thereby impairing the recruitment of CXCL13 fibroblasts and blocking tertiary lymphoid structure (TLS) assembly, a key predictor of LUAD prognosis. Local sensory denervation restores TLS formation, enhances B and T cell-dependent immunity, and suppresses tumor growth. Cigarette smoke extract (CSE) further activates this neural circuit to accelerate LUAD progression. In CSE-exposed animals, pharmacologic CGRP blockade sensitizes tumors to immunotherapy and prolongs survival. Together, our findings uncover a neuroimmune axis linking nociceptive neurons, TLS, and LUAD and identify neurogenic inflammation as a mechanism by which smoking promotes lung tumorigenesis independent of somatic mutagenesis.
Subjects
CGRP
cancer immunology
cancer neuroscience
chemogenetics
cigarette smoking
genetically engineered mouse model
lung adenocarcinoma
macrophage
neuroimmune crosstalk
non-small cell lung cancer
sensory neuron
tertiary lymphoid structure
Type
journal article