Peri-neural invasion (PNI) is a well-established poor prognostic factor in multiple cancer types. However, the mechanisms driving the PNI's detrimental clinical effect remain elusive. Here, we provide clinical and mechanistic insights into PNI and cancer-induced injury of tumor-associated nerves (TANs) and their role in resistance to anti-PD-1 therapy. Our work demonstrates that poor response to anti-PD-1 therapy in cutaneous squamous cell carcinoma (cSCC), melanoma, and gastric cancer is associated with PNI and TANs injury. Ultrastructural electron microscopy analysis reveals that direct contact between cancer cells and nerve fibers leads to cancer-induced nerve injury (CINI) via myelin degradation. Injured neurons respond by autonomously initiating an interleukin (IL)-6 and interferon (IFN) type I inflammatory response. This inflammatory response alters the immune activity in the peri-neural niche in melanoma, cSCC, and pancreatic adenocarcinoma, leading to an immuno-suppressive activity aimed at nerve healing and regeneration. As the tumor grows, the CINI burden increases, the inflammatory signal within the niche becomes chronic, and eventually skews the general immune tone within the tumor microenvironment to a suppressive and exhaustive state. The CINI-driven anti-PD-1 resistance can be reversed by targeting multiple steps in the CINI signaling process: denervating the tumor, conditional knockout of the transcription factor mediating the injury signal within neurons (cKO-Atf3), knockout of the IFN-a receptor signaling (Ifnar1-/-), or by combining anti-PD-1 and anti-IL-6-receptor blockade. Our findings demonstrate the direct immuno-regulatory roles of TANs and their therapeutic potential.
from sddb import Catalog
cohort = Catalog().collection("geo-gse289745")
cohort.members # the 11 datasets as a table
print(cohort.licenses()) # check the terms before you download
sdatas = cohort.to_dict() # {uid: SpatialData}, cached locally
# or keep the .zarr files in a folder of your choice:
# sdatas = cohort.to_dict(dest="data/")Needs pip install lamindb and network access to the Lamin database, which is limited during the alpha. If it fails, use the Client tab.
import lamindb as ln
db = ln.DB("scverse/spatialdata-db")
coll = db.Collection.get(key="geo-gse289745")
coll.ordered_artifacts.to_dataframe() # the 11 members, ordered
# download every member .zarr to the local cache:
paths = [a.cache() for a in coll.ordered_artifacts.all()]# sddb client: download every member .zarr into data/
sddb-cli download --collection geo-gse289745 --dest data/Licenses: 11 NCBI GEO policy
@article{Baruch_2025,
title = {Cancer-induced nerve injury promotes resistance to anti-PD-1 therapy},
volume = {646},
ISSN = {1476-4687},
url = {http://dx.doi.org/10.1038/s41586-025-09370-8},
DOI = {10.1038/s41586-025-09370-8},
number = {8084},
journal = {Nature},
publisher = {Springer Science and Business Media LLC},
author = {Baruch, Erez N. and Gleber-Netto, Frederico O. and Nagarajan, Priyadharsini and Rao, Xiayu and Akhter, Shamima and Eichwald, Tuany and Xie, Tongxin and Balood, Mohammad and Adewale, Adebayo and Naara, Shorook and Sathishkumar, Hinduja N. and Islam, Shajedul and McCarthy, William and Mattson, Brandi J. and Ferrarotto, Renata and Wong, Michael K. and Davies, Michael A. and Jindal, Sonali and Basu, Sreyashi and Roversi, Karine and Nikpoor, Amin Reza and Ahmadi, Maryam and Ahmadi, Ali and Harwood, Catherine and Leigh, Irene and Gong, Dennis and Tallón de Lara, Paulino and Tao, Derrick L. and Davidson, Tara M. and Ajami, Nadim J. and Futreal, Andrew and Rai, Kunal and Kochat, Veena and Castillo, Micah and Gunaratne, Preethi and Goepfert, Ryan P. and Hernandez, Sharia D. and Khushalani, Nikhil I. and Wang, Jing and Watowich, Stephanie S. and Calin, George A. and Migden, Michael R. and Yuan, Mona and Liu, Naijiang and Ye, Yi and Hwang, William L. and Vermeer, Paola D. and D’Silva, Nisha J. and Bunimovich, Yuri L. and Yaniv, Dan and Burks, Jared K. and Gomez, Javier and Dougherty, Patrick M. and Tsai, Kenneth Y. and Allison, James P. and Sharma, Padmanee and Wargo, Jennifer A. and Myers, Jeffrey N. and Talbot, Sebastien and Gross, Neil D. and Amit, Moran},
year = {2025},
month = Aug,
pages = {462–473}
}