Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy

  • Nature. 2025 Oct;646(8084):462-473. doi: 10.1038/s41586-025-09370-8.
Erez N Baruch  #  1  2 ,  Frederico O Gleber-Netto  #  3 ,  Priyadharsini Nagarajan  #  4 ,  Xiayu Rao  #  5 ,  Shamima Akhter  #  3 ,  Tuany Eichwald  #  6  7 ,  Tongxin Xie  3 ,  Mohammad Balood  7 ,  Adebayo Adewale  3 ,  Shorook Naara  3 ,  Hinduja N Sathishkumar  3 ,  Shajedul Islam  3 ,  William McCarthy  3 ,  Brandi J Mattson  8 ,  Renata Ferrarotto  9 ,  Michael K Wong  10 ,  Michael A Davies  10 ,  Sonali Jindal  11 ,  Sreyashi Basu  11 ,  Karine Roversi  7 ,  Amin Reza Nikpoor  7 ,  Maryam Ahmadi  7 ,  Ali Ahmadi  7 ,  Catherine Harwood  12  13 ,  Irene Leigh  12  13 ,  Dennis Gong  14  15  16 ,  Paulino Tallón de Lara  1  17 ,  Derrick L Tao  1 ,  Tara M Davidson  1 ,  Nadim J Ajami  2 ,  Andrew Futreal  18 ,  Kunal Rai  18 ,  Veena Kochat  18 ,  Micah Castillo  19 ,  Preethi Gunaratne  19 ,  Ryan P Goepfert  2 ,  Sharia D Hernandez  20 ,  Nikhil I Khushalani  21 ,  Jing Wang  22 ,  Stephanie S Watowich  23 ,  George A Calin  17  20 ,  Michael R Migden  24 ,  Mona Yuan  25  26 ,  Naijiang Liu  25  26 ,  Yi Ye  25  26 ,  William L Hwang  14  15 ,  Paola D Vermeer  27 ,  Nisha J D'Silva  28  29 ,  Yuri L Bunimovich  30  31 ,  Dan Yaniv  3 ,  Jared K Burks  32 ,  Javier Gomez  32 ,  Patrick M Dougherty  33 ,  Kenneth Y Tsai  34  35 ,  James P Allison  11  23 ,  Padmanee Sharma  11  23 ,  Jennifer A Wargo  2  18  36 ,  Jeffrey N Myers  3 ,  Sebastien Talbot  37  38 ,  Neil D Gross  39 ,  Moran Amit  40  41  42  43
Affiliations
  • 1. Division of Cancer Medicine, Hematology and Oncology Fellowship program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 2. Platform for Innovative Microbiome and Translational Research, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 3. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4. Department of Anatomical Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 5. Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
  • 7. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
  • 8. The Neurodegeneration Consortium, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 9. Department of Head and Neck Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 10. Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 11. James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 12. Department of Dermatology, Royal London Hospital, Barts Health NHS Trust, London, UK.
  • 13. Centre for Cell Biology and Cutaneous Research, Blizard Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • 14. Center for Systems Biology, Krantz Family Center for Cancer Research, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
  • 15. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 16. Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 17. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 18. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 19. Department of Biology and Biochemistry, University of Houston Sequencing and Gene Editing Core, University of Houston, Houston, TX, USA.
  • 20. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 21. Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
  • 22. Department of Bioinformatics and Computational Biology, Division of Discovery Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 23. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 24. Department of Dermatology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 25. Translational Research Center, New York University College of Dentistry, New York, NY, USA.
  • 26. Pain Research Center, Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA.
  • 27. Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA.
  • 28. Department of Periodontics and Oral Medicine, The University of Michigan, Ann Arbor, MI, USA.
  • 29. Department of Pathology, The University of Michigan, Ann Arbor, MI, USA.
  • 30. Department of Dermatology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 31. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 32. Department of Hematopoietic Biology & Malignancies, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 33. Department of Pain Medicine, Division of Anesthesiology, Critical Care, and Pain Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 34. Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. [email protected].
  • 35. Department of Tumor Microenvironment & Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA. [email protected].
  • 36. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 37. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. [email protected].
  • 38. Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada. [email protected].
  • 39. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 40. Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 41. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • 42. UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. [email protected].
  • 43. Cancer Neuroscience Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. [email protected].
  • # Contributed equally.
PMID: 40836096 DOI: 10.1038/s41586-025-09370-8
Abstract

Perineural invasion (PNI) is a well-established factor of poor prognosis in multiple Cancer types1, yet its mechanism remains unclear. Here we provide clinical and mechanistic insights into the role of PNI and cancer-induced nerve injury (CINI) in resistance to anti-PD-1 therapy. Our study demonstrates that PNI and CINI of tumour-associated nerves are associated with poor response to anti-PD-1 therapy among patients with cutaneous Squamous Cell Carcinoma, Melanoma and Gastric Cancer. Electron microscopy and electrical conduction analyses reveal that Cancer cells degrade the nerve fibre myelin sheets. The injured neurons respond by autonomously initiating IL-6- and type I interferon-mediated inflammation to promote nerve healing and regeneration. As the tumour grows, the CINI burden increases, and its associated inflammation becomes chronic and skews the general immune tone within the tumour microenvironment into a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signalling process: denervating the tumour, conditional knockout of the transcription factor mediating the injury signal within neurons (Atf3), knockout of interferon-α receptor signalling (IFNAR1-/-) or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immunoregulatory roles of CINI and its therapeutic potential.