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

Cell Research volume 35, pages 362–380 (2025)Cite this article

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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.

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Fig. 1: Ablation of nociceptor neurons suppresses PDAC development and cancer pain.
Fig. 2: Ablation of nociceptor neurons improves the infiltration and cytotoxic function of NK cells.
Fig. 3: NK cells but not T cells mediated the inhibitory effect of nociceptor neurons on PDAC.
Fig. 4: CGRP modulates NK cells contributing to PDAC progression.
Fig. 5: IL-15 mediates the modulation of CGRP on NK cells.
Fig. 6: CGPR inhibits IL-15 secretion from CAFs.
Fig. 7: Interaction of nociceptive neurons with CAFs to suppress NK cells.
Fig. 8: Negative correlation of nociceptive innervation with survival of PDAC patients.

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Data availability

Deidentified scRNA-seq raw data are available from the National Genomics Data Center (https://ngdc.cncb.ac.cn/subcenter/1) under accession number OEP005530 (Shared URL: https://www.biosino.org/node/project/detail/OEP005530). Further information related to the data reported in this paper can be acquired from the lead contact Jihui Hao (haojihui@tjmuch.com) upon reasonable request.

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Acknowledgements

The authors would thank Prof. Zilong Wang (Southern University of Science and Technology, China) for providing TRPV1-Cre and DTR mice. This work was funded by the National Natural Science Foundation of China (82030092 and 82273362), Major Project of Tianjin Public Health Science and Technology Program (24ZXGZSY00020), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), and State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine Project (QZ23-1).

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  1. These authors contributed equally: Kaiyuan Wang, Bo Ni, Yongjie Xie.

Authors and 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

    Kaiyuan Wang & Limei Yuan

  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

    Bo Ni, Yongjie Xie, Zekun Li, Chenyang Meng, Tiansuo Zhao, Song Gao, Chongbiao Huang, Hongwei Wang, Ying Ma, Tianxing Zhou, Yukuan Feng, Antao Chang, Chao Yang, Jun Yu, Wenwen Yu, Fenglin Zang, Yanhui Zhang, Xiuchao Wang & Jihui Hao

  3. Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA

    Ru-Rong Ji

  4. Department of Cell Biology, Duke University Medical Center, Durham, NC, USA

    Ru-Rong Ji

  5. Department of Neurobiology, Duke University Medical Center, Durham, NC, USA

    Ru-Rong Ji

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Contributions

J.H., R.R.J., X.W., and K.W. conceived and designed the study. K.W., B.N., Y.X., Z.L., L.Y., C.M., S.G., H.W., Y.M., T.X.Z., W.Y., F.Z., and Y.Z. performed the experiments. C.H., Y.X., T.S.Z., Y.F., A.C., C.Y., and J.Y. carried out data analysis. K.W. and X.W. wrote the first drafts of the manuscript; R.R.J. and J.H. edited the manuscript. Illustrations were created by B.N. and Y.X. using BioRender. All authors had full access to the data and approved the final version. J.H., X.W., R.R.J., and K.W. were responsible for the decision to submit the manuscript.

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Correspondence to Kaiyuan Wang, Ru-Rong Ji, Xiuchao Wang or Jihui Hao.

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Wang, K., Ni, B., Xie, Y. et al. Nociceptor neurons promote PDAC progression and cancer pain by interaction with cancer-associated fibroblasts and suppression of natural killer cells. Cell Res 35, 362–380 (2025). https://doi.org/10.1038/s41422-025-01098-4

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