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REVIEW article

Front. Immunol.

Sec. Cancer Immunity and Immunotherapy

Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1650117

Perineural Invasion and the "Cold" Tumor Microenvironment in Pancreatic Cancer: Mechanisms of Crosstalk and Therapeutic Opportunities

Provisionally accepted
Jianbiao  XuJianbiao Xu1Hong  YaoHong Yao1Junfeng  WangJunfeng Wang1Yun  JinYun Jin1Wei  ChangWei Chang2Lanjiang  LiLanjiang Li2Lei  ZouLei Zou3*
  • 1Kunming University of Science and Technology, Kunming, China
  • 2Kunming Medical University, Kunming, China
  • 3Faculty of Science, Kunming University of Science and Technology, Kunming, China

The final, formatted version of the article will be published soon.

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating malignancy characterized by profound lethality, aggressive local invasion, dismal prognosis, and significant resistance to existing therapies. Two critical biological features underpin the challenges in treating PDAC: extensive perineural invasion (PNI), the process by which cancer cells infiltrate and migrate along nerves, and a profoundly immunosuppressive, or "cold," tumor microenvironment (TME). PNI is not only a primary route for local tumor dissemination and recurrence but also a major contributor to the severe pain often experienced by patients. Concurrently, the PDAC TME is typified by a dense desmoplastic stroma, hypoxia, and an abundance of immunosuppressive cells-including cancerassociated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs)-while lacking sufficient infiltration of effector T cells, rendering it largely unresponsive to immunotherapies like checkpoint inhibitors. Although historically studied as separate entities, accumulating evidence reveals a deep-seated and complex bidirectional crosstalk between the neural components involved in PNI and the immune and stromal cells constituting the TME. Key cellular mediators, such as CAFs and TAMs, and shared signaling pathways, including the CXCL12/CXCR4 axis, TGF-β signaling, and neurotrophin pathways (e.g., NGF/TrkA), appear to act as critical nodes, coordinating the progression of PNI while simultaneously shaping and maintaining the immunosuppressive TME. This review synthesizes the current understanding of these intricate neuro-immune interactions in PDAC. We delineate the molecular and cellular mechanisms governing this crosstalk and explore how targeting these shared regulatory networks presents novel therapeutic opportunities, potentially disrupting PNI while concurrently "heating" the cold TME to overcome immunotherapy resistance. Elucidating this interplay is crucial not only for a deeper comprehension of PDAC's invasive and metastatic mechanisms but also for uncovering new therapeutic vulnerabilities to improve patient outcomes.

Keywords: Pancreatic Ductal Adenocarcinoma, Perineural invasion, Tumor Microenvironment, Immunosuppression, neuro-immune crosstalk, cancer-associated fibroblasts, Tumor-associated macrophages, CXCL12/CXCR4

Received: 19 Jun 2025; Accepted: 01 Aug 2025.

Copyright: © 2025 Xu, Yao, Wang, Jin, Chang, Li and Zou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Lei Zou, Faculty of Science, Kunming University of Science and Technology, Kunming, China

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