Spatial epigenomic landscape of NF-PanNETs defines tumor progression and microenvironmental niches

Non-functional pancreatic neuroendocrine tumors (NF-PanNETs) display substantial clinical and biological heterogeneity, yet the epigenetic mechanisms and spatial contexts that shape this diversity remain poorly defined. To address this gap, we performed an integrated analysis combining single-nucleus ATAC-seq (snATAC-seq) with spatial ATAC-seq across tumors of varying grades. snATAC-seq resolves chromatin accessibility landscapes for distinct tumor subtypes, immune populations, and cancer-associated fibroblasts (CAFs), uncovering transcription factor (TF) programs that underpin tumor progression and modulate microenvironmental interactions. Spatial ATAC-seq adds a critical layer of context, revealing two major tumor-stroma ecological niches: a proliferative niche characterized by E2F, MYC, and mTORC1 signaling, and an invasive niche enriched for Snail family TFs and KRAS pathway activation. These spatially anchored regulatory circuits highlight how NF-PanNET cell states emerge from the interplay between intrinsic epigenetic programs and local tissue environments. Collectively, our study establishes a spatially resolved epigenomic framework for dissecting NF-PanNET heterogeneity and evolution, providing new biomarkers, regulatory axes, and mechanistic insights with implications for molecular stratification and precision therapy.