Epigenetic Subtypes of High-Grade T1 Bladder Cancer Reveal Intra-Tumor Heterogeneity and Distinct Interactions with Tumor Microenvironment [scATAC-Seq]

Notably, ∼40% of URO tumors exhibited spatially distinct coexisting LLI and BL components. BL regions showed enrichment for angiogenesis and hypoxia pathways and were preferentially located near vascular stroma, while LLI regions showed to be located at the core of the tumor. MP tumors featured a markedly different microenvironment, characterized by diverse populations of cancer-associated fibroblasts (CAFs) and M2-polarized macrophages intermingled with tumor cells, suggesting a more immunosuppressive niche which could account for their worse clinical outcome.

URO tumors, by comparison, showed a more immune-excluded phenotype. These findings provide a detailed molecular and spatial map of bladder cancer heterogeneity, highlighting how distinct epigenetic subtypes and histological variants are associated with tumor architecture and microenvironmental interactions. Our data underscore the need for subtype-specific therapeutic strategies to more effectively address the complexity already existing at HGT1 bladder cancer.