Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer PMID: 42161272

ADC Targets in Oncology

2026-04-10

Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

Cell. 2026 May 19:S0092-8674(26)00505-2. doi: 10.1016/j.cell.2026.04.038.

Ya-Hsuan Ho ¹ , Giacomo Bregni ¹ , Marco Stazi ¹ , Paola Peinado ¹ , Pei-Hsing Chen ² , Claudio Ballabio ¹ , Victoire Boulat ³ , Shree Vadera ¹ , Yilin Guan ¹ , Zhikai Liu ⁴ , Alicia Alonso de la Vega ⁵ , Li Wang ⁶ , Chao-Chi Ho ⁷ , Henrique Veiga-Fernandes ⁸ , Julian Downward ⁵ , Min-Shu Hsieh ⁹ , Maksym V Kopanitsa ¹ , George Kassiotis ¹⁰ , Christoforos Tsantoulas ¹ , Michael S Schappe ¹¹ , Michael-Bogdan Margineanu ¹² , Dinis Pedro Calado ³ , Isaac M Chiu ¹³ , Charles Swanton ¹⁴ , Jin-Shing Chen ² , Leanne Li ¹⁵

Affiliations

1. Cancer Neuroscience Laboratory, Francis Crick Institute, London NW1 1AT, UK.
2. Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100225, Taiwan.
3. Immunity and Cancer Laboratory, Francis Crick Institute, London NW1 1AT, UK.
4. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
5. Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK.
6. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
7. Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100225, Taiwan.
8. Immunophysiology Group, Champalimaud Foundation, Lisbon 1400-038, Portugal.
9. Department of Pathology, National Taiwan University Hospital, Taipei 10025, Taiwan.
10. Retroviral Immunology Laboratory, Francis Crick Institute, London NW1 1AT, UK.
11. Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular & Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
12. Cancer Neuroscience Laboratory, Francis Crick Institute, London NW1 1AT, UK; Center of Immuno-Physiology and Biotechnologies, Department of Functional Sciences, "Victor Babes" University of Medicine and Pharmacy, Timisoara 300041, Romania.
13. Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
14. Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6DD, UK; Department of Oncology, University College London Hospitals, London WC1E 6AG, UK.
15. Cancer Neuroscience Laboratory, Francis Crick Institute, London NW1 1AT, UK. Electronic address: [email protected].

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.

Keywords

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.