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Peer-reviewedCC BYCell

Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer

  • Ya‐Hsuan Ho1
  • Giacomo Bregni1
  • Marco Stazi1
  • Paola Peinado1
  • Pei‐Hsing Chen2
  • Claudio Ballabio1
  • Victoire Boulat3
  • Shree Vadera1
  • Yilin Guan1
  • Zhikai Liu4
  • Alicia Alonso de la Vega5
  • Li Wang6
14 more authors
  • Chao‐Chi Ho7
  • Henrique Veiga‐Fernandes8
  • Julian Downward5
  • Min‐Shu Hsieh9
  • Maksym V. Kopanitsa1
  • George Kassiotis10
  • Christoforos Tsantoulas1
  • Michael S. Schappe11
  • Michael Margineanu12
  • Dinis Pedro Calado3
  • Isaac M. Chiu13
  • Charles Swanton14
  • Jin‐Shing Chen2
  • Leanne Li15
15 affiliations
  1. 1Cancer Neuroscience Laboratory, Francis Crick Institute, London NW1 1AT, UK
  2. 2Division of Thoracic Surgery, Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100225, Taiwan
  3. 3Immunity and Cancer Laboratory, Francis Crick Institute, London NW1 1AT, UK
  4. 4Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
  5. 5Oncogene Biology Laboratory, Francis Crick Institute, London NW1 1AT, UK
  6. 6Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA
  7. 7Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100225, Taiwan
  8. 8Immunophysiology Group, Champalimaud Foundation, Lisbon 1400-038, Portugal
  9. 9Department of Pathology, National Taiwan University Hospital, Taipei 10025, Taiwan
  10. 10Retroviral Immunology Laboratory, Francis Crick Institute, London NW1 1AT, UK
  11. 11Department 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. 12Cancer 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. 13Department of Immunology, Harvard Medical School, Boston, MA 02115, USA
  14. 14Cancer 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. 15Cancer Neuroscience Laboratory, Francis Crick Institute, London NW1 1AT, UK. Electronic address: [email protected]
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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.

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Cite

BibTeXRIS
BibTeX
@article{ho2026nociceptive,
  title = {{Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer}},
  author = {Ya‐Hsuan Ho and Giacomo Bregni and Marco Stazi and Paola Peinado and Pei‐Hsing Chen and Claudio Ballabio and Victoire Boulat and Shree Vadera and Yilin Guan and Zhikai Liu and Alicia Alonso de la Vega and Li Wang and Chao‐Chi Ho and Henrique Veiga‐Fernandes and Julian Downward and Min‐Shu Hsieh and Maksym V. Kopanitsa and George Kassiotis and Christoforos Tsantoulas and Michael S. Schappe and Michael Margineanu and Dinis Pedro Calado and Isaac M. Chiu and Charles Swanton and Jin‐Shing Chen and Leanne Li},
  journal = {Cell},
  year = {2026},
  month = may,
  doi = {10.1016/j.cell.2026.04.038},
  url = {https://doi.org/10.1016/j.cell.2026.04.038},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Nociceptive innervation limits tertiary lymphoid structures to promote lung cancer
AU  - Ya‐Hsuan Ho
AU  - Giacomo Bregni
AU  - Marco Stazi
AU  - Paola Peinado
AU  - Pei‐Hsing Chen
AU  - Claudio Ballabio
AU  - Victoire Boulat
AU  - Shree Vadera
AU  - Yilin Guan
AU  - Zhikai Liu
AU  - Alicia Alonso de la Vega
AU  - Li Wang
AU  - Chao‐Chi Ho
AU  - Henrique Veiga‐Fernandes
AU  - Julian Downward
AU  - Min‐Shu Hsieh
AU  - Maksym V. Kopanitsa
AU  - George Kassiotis
AU  - Christoforos Tsantoulas
AU  - Michael S. Schappe
AU  - Michael Margineanu
AU  - Dinis Pedro Calado
AU  - Isaac M. Chiu
AU  - Charles Swanton
AU  - Jin‐Shing Chen
AU  - Leanne Li
PY  - 2026
DA  - 2026/05/19
JO  - Cell
DO  - 10.1016/j.cell.2026.04.038
UR  - https://doi.org/10.1016/j.cell.2026.04.038
AB  - 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.
SN  - 0092-8674
SN  - 1097-4172
ER  -