Faculty, Staff and Student Publications

Language

English

Publication Date

10-1-2025

Journal

Nature

DOI

10.1038/s41586-025-09370-8

PMID

40836096

PMCID

PMC12406299

PubMedCentral® Posted Date

8-20-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Programmed Cell Death 1 Receptor, Mice, Humans, Drug Resistance, Neoplasm, Female, Male, Interleukin-6, Melanoma, Interferon Type I, Tumor Microenvironment, Receptor, Interferon alpha-beta, Stomach Neoplasms, Skin Neoplasms, Peripheral Nerve Injuries, Carcinoma, Squamous Cell, Inflammation, Signal Transduction, Immune Checkpoint Inhibitors, Neurons, Neoplasms, Neoplasm Invasiveness, Tumour immunology, Cancer microenvironment, Immunotherapy, Neuroimmunology, Squamous cell carcinoma

Published Open-Access

yes

Download

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.