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

Erez N. Baruch, Frederico O. Gleber-Netto, Priyadharsini Nagarajan, Xiayu Rao, Shamima Akhter, Tuany Eichwald, Tongxin Xie, Mohammad Balood, Adebayo Adewale, Shorook Naara, Hinduja N. Sathishkumar, Shajedul Islam, William McCarthy, Brandi J. Mattson, Renata Ferrarotto, Michael K. Wong, Michael A. Davies, Sonali Jindal, Sreyashi Basu, Karine Roversi, Amin Reza Nikpoor, Maryam Ahmadi, Ali Ahmadi, Catherine Harwood, Irene Leigh, Dennis Gong, Paulino Tallón de Lara, Derrick L. Tao, Tara M. Davidson, Nadim J. Ajami, Andrew Futreal, Kunal Rai, Veena Kochat, Micah Castillo, Preethi Gunaratne, Ryan P. Goepfert, Sharia D. Hernandez, Nikhil I. Khushalani, Jing Wang (), Stephanie S. Watowich, George A. Calin, Michael R. Migden, Mona Yuan, Naijiang Liu, Yi Ye, William L. Hwang, Paola D. Vermeer, Nisha J. D’Silva, Yuri L. Bunimovich, Dan Yaniv, Jared K. Burks, Javier Gomez, Patrick M. Dougherty, Kenneth Y. Tsai (), James P. Allison, Padmanee Sharma, Jennifer A. Wargo, Jeffrey N. Myers, Sebastien Talbot (), Neil D. Gross () and Moran Amit ()
Additional contact information
Erez N. Baruch: The University of Texas MD Anderson Cancer Center
Frederico O. Gleber-Netto: The University of Texas MD Anderson Cancer Center
Priyadharsini Nagarajan: The University of Texas MD Anderson Cancer Center
Xiayu Rao: The University of Texas MD Anderson Cancer Center
Shamima Akhter: The University of Texas MD Anderson Cancer Center
Tuany Eichwald: Karolinska Institutet
Tongxin Xie: The University of Texas MD Anderson Cancer Center
Mohammad Balood: Queen’s University
Adebayo Adewale: The University of Texas MD Anderson Cancer Center
Shorook Naara: The University of Texas MD Anderson Cancer Center
Hinduja N. Sathishkumar: The University of Texas MD Anderson Cancer Center
Shajedul Islam: The University of Texas MD Anderson Cancer Center
William McCarthy: The University of Texas MD Anderson Cancer Center
Brandi J. Mattson: University of Texas MD Anderson Cancer Center
Renata Ferrarotto: The University of Texas MD Anderson Cancer Center
Michael K. Wong: The University of Texas MD Anderson Cancer Center
Michael A. Davies: The University of Texas MD Anderson Cancer Center
Sonali Jindal: The University of Texas MD Anderson Cancer Center
Sreyashi Basu: The University of Texas MD Anderson Cancer Center
Karine Roversi: Queen’s University
Amin Reza Nikpoor: Queen’s University
Maryam Ahmadi: Queen’s University
Ali Ahmadi: Queen’s University
Catherine Harwood: Barts Health NHS Trust
Irene Leigh: Barts Health NHS Trust
Dennis Gong: Harvard Medical School
Paulino Tallón de Lara: The University of Texas MD Anderson Cancer Center
Derrick L. Tao: The University of Texas MD Anderson Cancer Center
Tara M. Davidson: The University of Texas MD Anderson Cancer Center
Nadim J. Ajami: The University of Texas MD Anderson Cancer Center
Andrew Futreal: The University of Texas MD Anderson Cancer Center
Kunal Rai: The University of Texas MD Anderson Cancer Center
Veena Kochat: The University of Texas MD Anderson Cancer Center
Micah Castillo: University of Houston
Preethi Gunaratne: University of Houston
Ryan P. Goepfert: The University of Texas MD Anderson Cancer Center
Sharia D. Hernandez: The University of Texas MD Anderson Cancer Center
Nikhil I. Khushalani: H. Lee Moffitt Cancer Center & Research Institute
Jing Wang: The University of Texas MD Anderson Cancer Center
Stephanie S. Watowich: The University of Texas MD Anderson Cancer Center
George A. Calin: The University of Texas MD Anderson Cancer Center
Michael R. Migden: The University of Texas MD Anderson Cancer Center
Mona Yuan: New York University College of Dentistry
Naijiang Liu: New York University College of Dentistry
Yi Ye: New York University College of Dentistry
William L. Hwang: Harvard Medical School
Paola D. Vermeer: Sanford Research
Nisha J. D’Silva: The University of Michigan
Yuri L. Bunimovich: University of Pittsburgh
Dan Yaniv: The University of Texas MD Anderson Cancer Center
Jared K. Burks: The University of Texas MD Anderson Cancer Center
Javier Gomez: The University of Texas MD Anderson Cancer Center
Patrick M. Dougherty: The University of Texas MD Anderson Cancer Center
Kenneth Y. Tsai: H. Lee Moffitt Cancer Center & Research Institute
James P. Allison: The University of Texas MD Anderson Cancer Center
Padmanee Sharma: The University of Texas MD Anderson Cancer Center
Jennifer A. Wargo: The University of Texas MD Anderson Cancer Center
Jeffrey N. Myers: The University of Texas MD Anderson Cancer Center
Sebastien Talbot: Karolinska Institutet
Neil D. Gross: The University of Texas MD Anderson Cancer Center
Moran Amit: The University of Texas MD Anderson Cancer Center

Nature, 2025, vol. 646, issue 8084, 462-473

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41586-025-09370-8

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