SLC25A16 and neoplasm: Despite advances in molecular classification, patient stratification still relies mainly on clinicopathological features, providing limited precision.<h4>Methods</h4>In this study, we integrated bulk chromatin profiling with single-nuclei RNA-seq, immunohistochemistry, and spatial transcriptomics to define epigenetic subtypes of HGT1, characterize their heterogeneity, and explore tumor-microenvironment interactions.<h4>Results</h4>We identified distinct chromatin landscapes distinguishing urothelial (URO) and micropapillary (MP) histological variants of high-risk HGT1.