Perineural invasion and the “cold” tumor microenvironment in pancreatic cancer: mechanisms of crosstalk and therapeutic opportunities

作者：Jianbiao Xu, Hong Yao, Junfeng Wang, Yun Jin, Wei Chang, Lanjiang Li, Lei Zou · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1650117 · 被引用次数：20 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Immune cells in cancer、Cancer Immunotherapy and Biomarkers

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 cancer-associated 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 pr...