Stroma-nerve axis in pancreatic ductal adenocarcinoma: Bidirectional regulatory mechanisms and clinical translation hypothesis

Abstract

Pancreatic ductal adenocarcinoma has a dismal five-year survival rate of less than 12%, with therapeutic resistance stemming from its distinctive “cold tumor” microenvironment characterized by neural infiltration, stromal remodeling, and immune suppression - elements that urgently require an integrated framework. On the basis of mechanistic, histopathological, and clinical correlative evidence, this narrative review reveals bidirectional coupling among tumor-associated nerve fibers, cancer-associated fibroblasts, and immune cells, forming a “neuro-stromal-immune” network that promotes tumor progression. Here, we propose the “stroma-nerve axis (SNA)” framework, which conceptualizes nerve fibers and stromal cells as functional units of the pancreatic ductal adenocarcinoma microenvironment, and construct a hypothesis of SNA activation stratification: Three hypothetical subtypes (nerve-dominant SNA-I, stroma-dominant SNA-II, and balanced SNA-III) corresponding to distinct invasion patterns, immune ecologies, and therapeutic windows. Furthermore, we propose a conceptual SNA Activity Score centered on neural density, cancer-associated fibroblast activation, and inflammatory signaling as a hypothesis-generating tool for future research. We emphasize that the SNA Activity Score represents solely a theoretical model lacking prospective validation and cannot be applied to clinical decision-making. Finally, we critically analyze the evidence strength and limitations of the SNA framework and recommend testing this hypothesis through spatial omics, bioinformatics, and prospective studies.

Keywords: Pancreatic ductal adenocarcinoma; Tumor microenvironment; Perineural invasion; Cancer-associated fibroblasts; Stroma-nerve axis

Core Tip: We propose the novel “stroma-nerve axis” framework, conceptualizing nerve fibers and stromal components as a functional unit driving pancreatic ductal adenocarcinoma progression. By defining three hypothetical stroma-nerve axis activation subtypes (nerve-dominant, stroma-dominant, and balanced) and a conceptual Stroma-Nerve Axis Activity Score, this review offers a unified theoretical model to explain therapeutic resistance. This perspective shifts the paradigm from single-target interventions to systematic “network dismantling” strategies, providing a roadmap for future stratified clinical trials.