Quantitative 3D histology reveals localized immune remodeling during early pancreatic cancer progression

Pancreatic cancer features a dense, immune-excluded stroma whose origins remain unclear. In this work, we extended CODA, a cellular-resolution three-dimensional (3D) histology pipeline, to map inflammation around more than 1,000 pancreatic precancers in large human pancreas specimens. Bulk analyses reproduce prior associations between overall inflammation and precancer burden, fibrosis, and acinar dropout, implicating ductal obstruction and stromal remodeling in early immune changes. Crucially, 3D mapping reveals that inflammation around individual precancers is highly heterogeneous, with immune hotspots and cold spots interchanging over tens of microns. Hotspots are found around regions of higher-grade dysplasia and ductal obstruction and are enriched for regulatory T cells and macrophages, indicating focal emergence of immunosuppression at the precancer stage. Integration with spatially resolved DNA sequencing implicated mutation in inflammation. These results position 3D mapping as a framework to identify rare sites of active microenvironmental priming and highlight focal immunosuppressive niches as candidate sites for early interception.