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.
This is a preview of subscription content, access via your institution
Access options
Access through your institution
Change institution
Buy or subscribe
Subscribe to this journal
Receive 12 digital issues and online access to articles
$119.00 per year
only $9.92 per issue
Learn more
Buy this article
Purchase on SpringerLink
Instant access to full article PDF
Buy now
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Log in
Learn about institutional subscriptions
Read our FAQs
Contact customer support
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.
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.
References
Monje, M. et al. Roadmap for the emerging field of cancer neuroscience. Cell 181, 219–222 (2020).
CASPubMedPubMed CentralGoogle Scholar
Winkler, F. et al. Cancer neuroscience: state of the field, emerging directions. Cell 186, 1689–1707 (2023).
CASPubMedPubMed CentralGoogle Scholar
Mancusi, R. & Monje, M. The neuroscience of cancer. Nature 618, 467–479 (2023).
CASPubMedPubMed CentralGoogle Scholar
Wang, K. et al. STING suppresses bone cancer pain via immune and neuronal modulation. Nat. Commun. 12, 4558 (2021).
CASPubMedPubMed CentralGoogle Scholar
Hanahan, D. & Monje, M. Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell 41, 573–580 (2023).
CASPubMedPubMed CentralGoogle Scholar
Shi, D. D. et al. Therapeutic avenues for cancer neuroscience: translational frontiers and clinical opportunities. Lancet Oncol. 23, e62–e74 (2022).
CASPubMedPubMed CentralGoogle Scholar
Ferdoushi, A. et al. Tumor innervation and clinical outcome in pancreatic cancer. Sci. Rep. 11, 7390 (2021).
CASPubMedPubMed CentralGoogle Scholar
Kondo, N. et al. An increased number of perineural invasions is independently associated with poor survival of patients with resectable pancreatic ductal adenocarcinoma. Pancreas 44, 1345–1351 (2015).
PubMedGoogle Scholar
Crippa, S. et al. Implications of perineural invasion on disease recurrence and survival after pancreatectomy for pancreatic head ductal adenocarcinoma. Ann. Surg. 276, 378–385 (2022).
PubMedGoogle Scholar
Hinshaw, D. C. & Shevde, L. A. The tumor microenvironment innately modulates cancer progression. Cancer Res. 79, 4557–4566 (2019).
CASPubMedPubMed CentralGoogle Scholar
Wang, H. et al. Role of the nervous system in cancers: a review. Cell Death Discov. 7, 76 (2021).
PubMedPubMed CentralGoogle Scholar
Demir, I. E. et al. Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis. EBioMedicine 46, 431–443 (2019).
CASPubMedPubMed CentralGoogle Scholar
Ceyhan, G. O. et al. Pancreatic neuropathy results in “neural remodeling” and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer. Am. J. Gastroenterol. 104, 2555–2565 (2009).
PubMedGoogle Scholar
Grossberg, A. J. et al. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J. Clin. 70, 375–403 (2020).
PubMedPubMed CentralGoogle Scholar
Ni, B. et al. Crosstalk between peripheral innervation and pancreatic ductal adenocarcinoma. Neurosci. Bull. 39, 1717–1731 (2023).
CASPubMedPubMed CentralGoogle Scholar
Saloman, J. L. et al. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl. Acad. Sci. USA 113, 3078–3083 (2016).
CASPubMedPubMed CentralGoogle Scholar
Sinha, S. et al. PanIN neuroendocrine cells promote tumorigenesis via neuronal cross-talk. Cancer Res. 77, 1868–1879 (2017).
CASPubMedPubMed CentralGoogle Scholar
Wu, M. et al. Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity. Cell 187, 2935–2951.e19 (2024).
CASPubMedGoogle Scholar
Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405–412 (2022).
CASPubMedPubMed CentralGoogle Scholar
Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097.e22 (2018).
CASPubMedPubMed CentralGoogle Scholar
Baral, P. et al. Nociceptor sensory neurons suppress neutrophil and γδ T cell responses in bacterial lung infections and lethal pneumonia. Nat. Med. 24, 417–426 (2018).
CASPubMedPubMed CentralGoogle Scholar
Tamari, M. et al. Sensory neurons promote immune homeostasis in the lung. Cell 187, 44–61.e17 (2024).
CASPubMedGoogle Scholar
Ceyhan, G. O. et al. Pancreatic neuropathy and neuropathic pain—a comprehensive pathomorphological study of 546 cases. Gastroenterology 136, 177–186.e1 (2009).
PubMedGoogle Scholar
Selvaraj, D., Hirth, M., Gandla, J. & Kuner, R. A mouse model for pain and neuroplastic changes associated with pancreatic ductal adenocarcinoma. Pain 158, 1609–1621 (2017).
PubMedGoogle Scholar
Li, L. et al. The impact of TRPV1 on cancer pathogenesis and therapy: a systematic review. Int J. Biol. Sci. 17, 2034–2049 (2021).
CASPubMedPubMed CentralGoogle Scholar
Lai, N. Y. et al. Gut-innervating nociceptor neurons regulate Peyer’s Patch Microfold cells and SFB levels to mediate Salmonella host defense. Cell 180, 33–49.e22 (2020).
CASPubMedGoogle Scholar
Wang, X. et al. Phenotype screens of murine pancreatic cancer identify a Tgf-α-Ccl2-paxillin axis driving human-like neural invasion. J. Clin. Invest. 133, e166333 (2023).
CASPubMedPubMed CentralGoogle Scholar
Makhmutova, M. & Caicedo, A. Optical imaging of pancreatic innervation. Front. Endocrinol. 12, 663022 (2021).
Google Scholar
Schwartz, E. S. et al. TRPV1 and TRPA1 antagonists prevent the transition of acute to chronic inflammation and pain in chronic pancreatitis. J. Neurosci. 33, 5603–5611 (2013).
CASPubMedPubMed CentralGoogle Scholar
Ma, Y. et al. Combination of PD-1 inhibitor and OX40 agonist induces tumor rejection and immune memory in mouse models of pancreatic cancer. Gastroenterology 159, 306–319.e12 (2020).
CASPubMedGoogle Scholar
Wang, K. et al. PD-1 blockade inhibits osteoclast formation and murine bone cancer pain. J. Clin. Invest. 130, 3603–3620 (2020).
CASPubMedPubMed CentralGoogle Scholar
Wakabayashi, H. et al. Decreased sensory nerve excitation and bone pain associated with mouse Lewis lung cancer in TRPV1-deficient mice. J. Bone Miner. Metab. 36, 274–285 (2018).
CASPubMedGoogle Scholar
Zhang, Y., Chen, M., Liu, Z., Wang, X. & Ji, T. The neuropeptide calcitonin gene-related peptide links perineural invasion with lymph node metastasis in oral squamous cell carcinoma. BMC Cancer 21, 1254 (2021).
CASPubMedPubMed CentralGoogle Scholar
Croop, R. et al. Oral rimegepant for preventive treatment of migraine: a phase 2/3, randomised, double-blind, placebo-controlled trial. Lancet 397, 51–60 (2021).
CASPubMedGoogle Scholar
Lipton, R. B. et al. Rimegepant, an oral calcitonin gene-related peptide receptor antagonist, for migraine. N. Engl. J. Med. 381, 142–149 (2019).
CASPubMedGoogle Scholar
Shimasaki, N., Jain, A. & Campana, D. NK cells for cancer immunotherapy. Nat. Rev. Drug Discov. 19, 200–218 (2020).
CASPubMedGoogle Scholar
Dean, I. et al. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat. Commun. 15, 683 (2024).
CASPubMedPubMed CentralGoogle Scholar
Wang, D. & Wei, H. Natural killer cells in tumor immunotherapy. Cancer Biol. Med. 20, 539–544 (2023).
PubMedPubMed CentralGoogle Scholar
Kurz, E. et al. Exercise-induced engagement of the IL-15/IL-15Rα axis promotes anti-tumor immunity in pancreatic cancer. Cancer Cell 40, 720–737.e5 (2022).
CASPubMedPubMed CentralGoogle Scholar
Rebelo, R., Xavier, C. P. R., Giovannetti, E. & Vasconcelos, M. H. Fibroblasts in pancreatic cancer: molecular and clinical perspectives. Trends Mol. Med. 29, 439–453 (2023).
CASPubMedGoogle Scholar
Li, X. et al. Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. Clin. Cancer Res. 20, 4326–4338 (2014).
CASPubMedGoogle Scholar
Stopczynski, R. E. et al. Neuroplastic changes occur early in the development of pancreatic ductal adenocarcinoma. Cancer Res. 74, 1718–1727 (2014).
CASPubMedPubMed CentralGoogle Scholar
Saloman, J. L. et al. Systemic depletion of nerve growth factor inhibits disease progression in a genetically engineered model of pancreatic ductal adenocarcinoma. Pancreas 47, 856–863 (2018).
CASPubMedPubMed CentralGoogle Scholar
Ye, Y., Xie, T. & Amit, M. Targeting the nerve-cancer circuit. Cancer Res. 83, 2445–2447 (2023).
CASPubMedGoogle Scholar
Wang, B. et al. Combinatorial sympathetic and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockades inhibit the murine melanoma growth by targeting infiltrating T cells. Transl. Cancer Res. 10, 899–913 (2021).
CASPubMedPubMed CentralGoogle Scholar
Globig, A. M. et al. The β(1)-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383–392 (2023).
CASPubMedPubMed CentralGoogle Scholar
Yang, M. W. et al. Perineural invasion reprograms the immune microenvironment through cholinergic signaling in pancreatic ductal adenocarcinoma. Cancer Res. 80, 1991–2003 (2020).
CASPubMedGoogle Scholar
Szallasi, A. Resiniferatoxin: Nature’s precision medicine to silence TRPV1-positive afferents. Int. J. Mol. Sci. 24, 15042 (2023).
CASPubMedPubMed CentralGoogle Scholar
Brown, D. C. Resiniferatoxin: The evolution of the “Molecular Scalpel” for chronic pain relief. Pharmaceuticals 9, 47 (2016).
PubMedPubMed CentralGoogle Scholar
Brown, D. C., Agnello, K. & Iadarola, M. J. Intrathecal resiniferatoxin in a dog model: efficacy in bone cancer pain. Pain 156, 1018–1024 (2015).
CASPubMedPubMed CentralGoogle Scholar
Schnittert, J., Bansal, R. & Prakash, J. Targeting pancreatic stellate cells in cancer. Trends Cancer 5, 128–142 (2019).
CASPubMedGoogle Scholar
Sparmann, G. et al. Inhibition of lymphocyte apoptosis by pancreatic stellate cells: impact of interleukin-15. Am. J. Physiol. Gastrointest. Liver Physiol. 289, G842–G851 (2005).
CASPubMedGoogle Scholar
Ma, S., Caligiuri, M. A. & Yu, J. Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy. Trends Immunol. 43, 833–847 (2022).
CASPubMedPubMed CentralGoogle Scholar
Vivier, E. et al. Natural killer cell therapies. Nature 626, 727–736 (2024).
CASPubMedGoogle Scholar
Renz, B. W. et al. β2 Adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 33, 75–90.e7 (2018).
CASPubMedGoogle Scholar
Ramer, M. S., Bradbury, E. J., Michael, G. J., Lever, I. J. & McMahon, S. B. Glial cell line-derived neurotrophic factor increases calcitonin gene-related peptide immunoreactivity in sensory and motoneurons in vivo. Eur. J. Neurosci. 18, 2713–2721 (2003).
PubMedGoogle Scholar
Kobayashi, H. et al. Neuro-mesenchymal interaction mediated by a β2 adrenergic-nerve growth factor feedforward loop promotes colorectal cancer progression. Cancer Discov. 15, 202–226 (2025).
PubMedGoogle Scholar
Bennett, M. I. Mechanism-based cancer-pain therapy. Pain 158, S74–S78 (2017).
PubMedGoogle Scholar
Schweizerhof, M. et al. Hematopoietic colony-stimulating factors mediate tumor-nerve interactions and bone cancer pain. Nat. Med. 15, 802–807 (2009).
CASPubMedGoogle Scholar
Selvaraj, D. et al. A functional role for VEGFR1 expressed in peripheral sensory neurons in cancer pain. Cancer Cell 27, 780–796 (2015).
CASPubMedPubMed CentralGoogle Scholar
Jimenez-Andrade, J. M., Ghilardi, J. R., Castañeda-Corral, G., Kuskowski, M. A. & Mantyh, P. W. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain 152, 2564–2574 (2011).
CASPubMedPubMed CentralGoogle Scholar
Zhao, T. et al. ESE3-positive PSCs drive pancreatic cancer fibrosis, chemoresistance and poor prognosis via tumour-stromal IL-1β/NF-κB/ESE3 signalling axis. Br. J. Cancer 127, 1461–1472 (2022).
CASPubMedPubMed CentralGoogle Scholar
Liu, J. et al. Tumoral EHF predicts the efficacy of anti-PD1 therapy in pancreatic ductal adenocarcinoma. J. Exp. Med. 216, 656–673 (2019).
CASPubMedPubMed CentralGoogle Scholar
Donnelly, C. R. et al. STING controls nociception via type I interferon signalling in sensory neurons. Nature 591, 275–280 (2021).
CASPubMedPubMed CentralGoogle Scholar
Luo, X. et al. IL-23/IL-17A/TRPV1 axis produces mechanical pain via macrophage-sensory neuron crosstalk in female mice. Neuron 109, 2691–2706.e5 (2021).
CASPubMedPubMed CentralGoogle Scholar
Lovell, M. R. et al. Effect of cancer pain guideline implementation on pain outcomes among adult outpatients with cancer-related pain: A stepped wedge cluster randomized trial. JAMA Netw. Open 5, e220060 (2022).
PubMedPubMed CentralGoogle Scholar
de Conno, F. et al. Pain measurement in cancer patients: a comparison of six methods. Pain 57, 161–166 (1994).
PubMedGoogle Scholar
Gerbershagen, H. J., Rothaug, J., Kalkman, C. J. & Meissner, W. Determination of moderate-to-severe postoperative pain on the numeric rating scale: a cut-off point analysis applying four different methods. Br. J. Anaesth. 107, 619–626 (2011).
CASPubMedGoogle Scholar
Download references
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).
Author information
Author notes
These authors contributed equally: Kaiyuan Wang, Bo Ni, Yongjie Xie.
Authors and Affiliations
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
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
Center for Translational Pain Medicine, Department of Anesthesiology, Duke University Medical Center, Durham, NC, USA
Ru-Rong Ji
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA
Ru-Rong Ji
Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
Ru-Rong Ji
Authors
Kaiyuan Wang
View author publications
You can also search for this author inPubMedGoogle Scholar
2. Bo Ni
View author publications
You can also search for this author inPubMedGoogle Scholar
3. Yongjie Xie
View author publications
You can also search for this author inPubMedGoogle Scholar
4. Zekun Li
View author publications
You can also search for this author inPubMedGoogle Scholar
5. Limei Yuan
View author publications
You can also search for this author inPubMedGoogle Scholar
6. Chenyang Meng
View author publications
You can also search for this author inPubMedGoogle Scholar
7. Tiansuo Zhao
View author publications
You can also search for this author inPubMedGoogle Scholar
8. Song Gao
View author publications
You can also search for this author inPubMedGoogle Scholar
9. Chongbiao Huang
View author publications
You can also search for this author inPubMedGoogle Scholar
10. Hongwei Wang
View author publications
You can also search for this author inPubMedGoogle Scholar
11. Ying Ma
View author publications
You can also search for this author inPubMedGoogle Scholar
12. Tianxing Zhou
View author publications
You can also search for this author inPubMedGoogle Scholar
13. Yukuan Feng
View author publications
You can also search for this author inPubMedGoogle Scholar
14. Antao Chang
View author publications
You can also search for this author inPubMedGoogle Scholar
15. Chao Yang
View author publications
You can also search for this author inPubMedGoogle Scholar
16. Jun Yu
View author publications
You can also search for this author inPubMedGoogle Scholar
17. Wenwen Yu
View author publications
You can also search for this author inPubMedGoogle Scholar
18. Fenglin Zang
View author publications
You can also search for this author inPubMedGoogle Scholar
19. Yanhui Zhang
View author publications
You can also search for this author inPubMedGoogle Scholar
20. Ru-Rong Ji
View author publications
You can also search for this author inPubMedGoogle Scholar
21. Xiuchao Wang
View author publications
You can also search for this author inPubMedGoogle Scholar
22. Jihui Hao
View author publications
You can also search for this author inPubMedGoogle Scholar
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.
Corresponding authors
Correspondence to Kaiyuan Wang, Ru-Rong Ji, Xiuchao Wang or Jihui Hao.
Ethics declarations
Competing interests
The authors declare no competing interests.
Supplementary information
Supplementary information, Fig. S1
Supplementary information, Fig. S2
Supplementary information, Fig. S3
Supplementary information, Fig. S4
Supplementary information, Fig. S5
Supplementary information, Fig. S6
Supplementary information, Fig. S7
Supplementary information, Fig. S8
Supplementary information, Fig. S9
Supplementary information, Fig. S10
Supplementary information, Fig. S11
Supplementary information, Fig. S12
Supplementary information, Fig. S13
Supplementary information, Fig. S14
Supplementary information, Fig. S15
Supplementary information, Fig. S16
Supplementary information, Fig. S17
Supplementary information, Table S1
Supplementary information, Table S2
Supplementary information, Table S3
Supplementary information, Data S1
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
Reprints and permissions
About this article
Check for updates. Verify currency and authenticity via CrossMark
Cite this article
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 (2025). https://doi.org/10.1038/s41422-025-01098-4
Download citation
Received:17 September 2024
Accepted:05 March 2025
Published:24 March 2025
DOI:https://doi.org/10.1038/s41422-025-01098-4
Share this article
Anyone you share the following link with will be able to read this content:
Get shareable link
Sorry, a shareable link is not currently available for this article.
Copy to clipboard
Provided by the Springer Nature SharedIt content-sharing initiative