Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

Publication information:

Ya-Hsuan Ho, Giacomo Bregni, Marco Stazi, Paola Peinado, Pei-Hsing Chen, Claudio Ballabio, Victoire Boulat, Shree Vadera, Yilin Guan, Zhikai Liu, Alicia Alonso de la Vega, Li Wang, Chao-Chi Ho, Henrique Veiga-Fernandes, Julian Downward, Min-Shu Hsieh, Maksym V. Kopanitsa, George Kassiotis, Christoforos Tsantoulas, Michael S. Schappe, Michael-Bogdan Margineanu, Dinis Pedro Calado, Isaac M. Chiu, Charles Swanton, Jin-Shing Chen, and Leanne Li. 2026. “Nociceptive Innervation Limits Tertiary Lymphoid Structures to Promote Lung Cancer”. Cell. doi:https://doi.org/10.1016/j.cell.2026.04.038

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.