Volume 35, No 5, May 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 5, May 2025: 362-380

ORIGINAL ARTICLES

Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells

Kaiyuan Wang^1,†,* , Bo Ni^2,† , Yongjie Xie^2,† , Zekun Li² , Limei Yuan¹ , Chenyang Meng² , Tiansuo Zhao² , Song Gao² , Chongbiao Huang² , Hongwei Wang² , Ying Ma² , Tianxing Zhou² , Yukuan Feng² , Antao Chang² , Chao Yang² , Jun Yu² , Wenwen Yu² , Fenglin Zang² , Yanhui Zhang² , Ru-Rong Ji^3,4,5,* , Xiuchao Wang^2,* , Jihui Hao^2,*

¹Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
²Pancreas Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, China
³Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
⁴Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
⁵Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
^†These authors contributed equally: Kaiyuan Wang, Bo Ni, Yongjie Xie
Correspondence: Kaiyuan Wang(kywang@tmu.edu.cn)Ru-Rong Ji(ru-rong.ji@duke.edu)Xiuchao Wang(wangxiuchao@tjmuch.com)Jihui Hao(haojihui@tjmuch.com)

The emerging field of cancer neuroscience has demonstrated great progress in revealing the crucial role of the nervous system in cancer initiation and progression. Pancreatic ductal adenocarcinoma (PDAC) is characterized by perineural invasion and modulated by autonomic (sympathetic and parasympathetic) and sensory innervations. Here, we further demonstrated that within the tumor microenvironment of PDAC, nociceptor neurons interacted with cancer-associated fibroblasts (CAFs) through calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF). This interaction led to the inhibition of interleukin-15 expression in CAFs, suppressing the infiltration and cytotoxic function of natural killer (NK) cells and thereby promoting PDAC progression and cancer pain. In PDAC patients, nociceptive innervation of tumor tissue is negatively correlated with the infiltration of NK cells while positively correlated with pain intensity. This association serves as an independent prognostic factor for both overall survival and relapse-free survival for PDAC patients. Our findings highlight the crucial regulation of NK cells by nociceptor neurons through interaction with CAFs in the development of PDAC. We also propose that targeting nociceptor neurons or CGRP signaling may offer a promising therapy for PDAC and cancer pain.

https://doi.org/10.1038/s41422-025-01098-4

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