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

  • Cell Res. 2025 May;35(5):362-380. doi: 10.1038/s41422-025-01098-4.
Kaiyuan Wang  #  1 ,  Bo Ni  #  2 ,  Yongjie Xie  #  2 ,  Zekun Li  2 ,  Limei Yuan  3 ,  Chenyang Meng  2 ,  Tiansuo Zhao  2 ,  Song Gao  2 ,  Chongbiao Huang  2 ,  Hongwei Wang  2 ,  Ying Ma  2 ,  Tianxing Zhou  2 ,  Yukuan Feng  2 ,  Antao Chang  2 ,  Chao Yang  2 ,  Jun Yu  2 ,  Wenwen Yu  2 ,  Fenglin Zang  2 ,  Yanhui Zhang  2 ,  Ru-Rong Ji  4  5  6 ,  Xiuchao Wang  7 ,  Jihui Hao  8
Affiliations
  • 1. Department 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. [email protected].
  • 2. Pancreas 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.
  • 3. Department 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.
  • 4. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA. [email protected].
  • 5. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA. [email protected].
  • 6. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. [email protected].
  • 7. Pancreas 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. [email protected].
  • 8. Pancreas 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. [email protected].
  • # Contributed equally.
PMID: 40122998 DOI: 10.1038/s41422-025-01098-4
Abstract

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.