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

Figure 1 Core mechanism of the stroma-nerve axis in pancreatic ductal adenocarcinoma. Schematic overview of reciprocal interactions between tumor cells, nerve fibers, cancer-associated fibroblasts (CAFs)/extracellular matrix and immune cells in pancreatic ductal adenocarcinoma. Tumor-derived factors (e.g., nerve growth factor, transforming growth factor-β, and interleukin-6) promote neurite outgrowth and CAF activation, whereas nerve-derived mediators (norepinephrine and neuropeptides) increase tumor proliferation and invasion. CAF/extracellular matrix remodeling and C-X-C motif chemokine 12/interleukin-6-driven immune suppression establish an immunosuppressive niche, forming a positive-feedback stroma-nerve axis that supports pancreatic ductal adenocarcinoma progression, immune escape and therapy resistance. NGF: Nerve growth factor; TGF: Transforming growth factor; PDAC: Pancreatic ductal adenocarcinoma; CAF: Cancer-associated fibroblasts; ECM: Extracellular matrix; CXCL12: C-X-C motif chemokine 12; IL: Interleukin; MDSC: Myeloid-derived suppressor cells.

Figure 2 Hypothetical stroma-nerve axis phenotypes in pancreatic ductal adenocarcinoma. Conceptual illustration of three stroma-nerve axis (SNA) activation patterns: SNA-I (nerve-dominant), with high nerve density, moderate stroma and sparse but suppressive immune infiltrates; SNA-II (stroma-dominant), with very dense cancer-associated fibroblast-rich stroma, low nerve prominence and an immune-excluded pattern; and SNA-III (balanced type), with intermediate nerve and stroma and a mixed immune infiltrate. The feature boxes summarize the relative levels of nerve activity, cancer-associated fibroblast/extracellular matrix and immune suppression/exclusion. These phenotypes are hypothesis-generating constructs and do not represent validated clinical subtypes. SNA: Stroma-nerve axis; CAF: Cancer-associated fibroblasts; ECM: Extracellular matrix.

Figure 3 Proposed research pathway for the Stroma-Nerve Axis Activity Score. The schematic outlines a stepwise framework from concept generation and definition of key stroma-nerve axis (SNA) dimensions through biomarker and data collection (pathology/immunohistochemistry, multiomics, and clinical outcomes) to the statistical/model-based construction of a SNA Activity Score prototype. Subsequent validation in independent cohorts and exploratory SNA-informed clinical trials (e.g., SNA-high vs SNA-low stratification) are illustrated. SNA Activity Score is presented as a conceptual research tool, and this pathway is intended for model development and hypothesis testing rather than immediate clinical decision-making. SNAAS: Stroma-Nerve Axis Activity Score; SNA: Stroma-nerve axis; CAF: Cancer-associated fibroblasts; ECM: Extracellular matrix; IHC: Immunohistochemistry.