Xu Jianbiao, Yao Hong, Wang Junfeng, Jin Yun, Chang Wei, Li Lanjiang, Zou Lei
Department of General Surgery, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
Department of Radiology, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China.
Front Immunol. 2025 Aug 20;16:1650117. doi: 10.3389/fimmu.2025.1650117. eCollection 2025.
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 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.
胰腺导管腺癌（PDAC）仍然是一种极具毁灭性的恶性肿瘤，其特征是致死率高、局部侵袭性强、预后不佳以及对现有疗法具有显著抗性。治疗PDAC面临的挑战有两个关键生物学特征：广泛的神经周围浸润（PNI），即癌细胞沿神经浸润和迁移的过程，以及深度免疫抑制或“冷”肿瘤微环境（TME）。PNI不仅是局部肿瘤扩散和复发的主要途径，也是患者常经历的剧痛的主要原因。同时，PDAC的TME的特点是有致密的促纤维增生性基质、缺氧以及大量免疫抑制细胞，包括癌症相关成纤维细胞（CAF）、肿瘤相关巨噬细胞（TAM）、骨髓来源的抑制细胞（MDSC）和调节性T细胞（Treg），而效应T细胞浸润不足，这使得它对诸如检查点抑制剂等免疫疗法基本无反应。尽管历史上它们被作为独立的实体进行研究，但越来越多的证据表明，参与PNI的神经成分与构成TME的免疫和基质细胞之间存在深层次且复杂的双向串扰。关键的细胞介质，如CAF和TAM，以及共同的信号通路，包括CXCL12/CXCR4轴、TGF-β信号通路和神经营养因子通路（如NGF/TrkA），似乎充当关键节点，协调PNI的进展，同时塑造和维持免疫抑制性TME。本综述综合了目前对PDAC中这些复杂的神经 - 免疫相互作用的理解。我们阐述了控制这种串扰的分子和细胞机制，并探讨了靶向这些共同的调控网络如何带来新的治疗机会，有可能破坏PNI，同时“加热”冷TME以克服免疫治疗抗性。阐明这种相互作用不仅对于更深入理解PDAC的侵袭和转移机制至关重要，而且对于发现新的治疗弱点以改善患者预后也至关重要。
