Sun S, Zhou RJ, Xiang SL, Zhang TT, Du JJ, Zhao HF, Xu YZ, Pan X, He XY, Zuo ZB. Prominent crosstalks between perineural invasion and immunosuppressive tumor microenvironment in pancreatic ductal adenocarcinoma. World J Clin Oncol 2026; 17(6): 121085 [DOI: 10.5306/wjco.121085]
Corresponding Author of This Article
Shuai Sun, Department of Pathology, Hangzhou Cancer Hospital, No. 34 Yanguan Lane, Shangcheng District, Hangzhou 310002, Zhejiang Province, China. sunshuai005@gmail.com
Research Domain of This Article
Oncology
Article-Type of This Article
review-article
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Shuai Sun, Rong-Jing Zhou, Ting-Ting Zhang, Jun-Jun Du, Hai-Fei Zhao, Department of Pathology, Hangzhou Cancer Hospital, Hangzhou 310002, Zhejiang Province, China
Si-Lin Xiang, Department of Graduate, Zhejiang Chinese Medical University, Hangzhou 310002, Zhejiang Province, China
Yan-Zhen Xu, Xiang-Yun He, Zhi-Bo Zuo, Department of Pathology, Westlake University Affiliated Hangzhou First People’s Hospital, Hangzhou 310002, Zhejiang Province, China
Xin Pan, Department of Pathology, Chun’an County First People’s Hospital, Hangzhou 310002, Zhejiang Province, China
Co-corresponding authors: Shuai Sun and Rong-Jing Zhou.
Author contributions: Sun S and Zhou RJ conceptualized and designed the study as co-corresponding authors; Sun S and Xiang SL performed the literature search and drafted the original manuscript; Zhang TT, Du JJ, Zhao HF, Xu YZ, Pan X, He XY, and Zuo ZB collected the data and assisted in figure preparation; Sun S, Zhou RJ, and Xiang SL critically revised the manuscript for important intellectual content; all authors have read and approved the final version of the manuscript.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Shuai Sun, Department of Pathology, Hangzhou Cancer Hospital, No. 34 Yanguan Lane, Shangcheng District, Hangzhou 310002, Zhejiang Province, China. sunshuai005@gmail.com
Received: March 16, 2026 Revised: April 28, 2026 Accepted: June 4, 2026 Published online: June 24, 2026 Processing time: 99 Days and 3 Hours
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with a 5-year overall survival of about 12%. Perineural invasion (PNI), documented in most surgical specimens, is a common hallmark of PDAC that drives cancer-associated pain, recurrence, and resistance to therapy. Far from a passive histological finding, PNI reflects an active, bidirectional program shaped by dynamic crosstalk between tumor cells, nerves, and the immunosuppressive tumor microenvironment. Cancer-associated fibroblasts, tumor-associated neutrophils, tumor-associated macrophages, and myeloid-derived suppressor cells each make distinctive contributions to the immunosuppressive perineural niche. We further delineate how PNI facilitates neural route metastasis, drives chemotherapy resistance through neurotrophic and immune mechanisms, and reprograms cellular metabolism in ways that concurrently support tumor invasion and impair anti-tumor immunity. Finally, we highlight promising therapeutic strategies targeting the neural-immune axis, including β-adrenergic blockade, neurotrophic receptor inhibition, immune checkpoint combination approaches, and metabolic interventions. These strategies may hold transformative potential for the management of PNI-positive PDAC.
Core Tip: Perineural invasion is a bidirectional program in pancreatic ductal adenocarcinoma. It is sustained by crosstalks between tumor cells, nerves, and the immunosuppressive tumor microenvironment. The cellular compartments in tumor microenvironment collectively establish an immunosuppressive perineural niche. This niche enables neural dissemination, chemotherapy resistance, and cancer-associated pain. Adrenergic and cholinergic signaling amplifies this immunosuppression. Schwann cells actively guide tumor migration along nerve trunks. Therapeutic strategies targeting the neural-immune axis hold transformative potential for pancreatic ductal adenocarcinoma management.
