Abstract
Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) account for the majority of neuroendocrine neoplasms arising in the pancreas and exhibit substantial clinical and biological heterogeneity, yet their epigenetic regulation and spatial architecture remain poorly understood. Here, we present an integrative study of NF-PanNETs across multiple tumor grades using single-nucleus ATAC-seq (snATAC-seq) and spatial ATAC-seq. snATAC-seq delineates the chromatin accessibility landscapes of distinct tumor subtypes, immune cells, and cancer-associated fibroblasts (CAFs), revealing key transcription factor (TF) programs that drive tumor progression and shape microenvironmental interactions. Spatial ATAC-seq further identifies two distinct tumor-stroma ecological niches: a proliferative niche marked by MYC and FOX family, and an invasive niche enriched for Snail family TFs and KRAS pathway activity. These findings demonstrate that cellular behavior in NF-PanNETs is governed not only by intrinsic epigenetic states but also by spatial context. Together, our study provides a spatially resolved epigenomic framework for dissecting NF-PanNET heterogeneity and evolution, offering new biomarkers and regulatory axes for molecular stratification and precision therapy.