Single-cell and spatial transcriptomics reveal SUV39H1 as a master epigenetic driver of immunosuppressive niche and stemness in bladder cancer

Bladder cancer (BC) exhibits profound molecular heterogeneity and a highly dynamic tumor microenvironment, posing major challenges for effective therapy. In this study, we leveraged single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, complemented by integrative multi-omics analysis and machine learning, to systematically dissect the cellular and spatial architecture of BC and uncover key regulatory drivers.We identified the histone methyltransferase SUV39H1 as a central epigenetic regulator strongly associated with tumor progression, stemness, and poor prognosis. At single-cell resolution, SUV39H1-high epithelial subpopulations displayed enhanced stemness features and were enriched in transcriptional programs linked to proliferation and immune modulation. Notably, these cells exhibited extensive ligand-receptor interactions with inflammatory fibroblasts, suggesting a critical role in shaping a pro-tumorigenic stromal niche.Spatial transcriptomic analysis further revealed that SUV39H1 expression is preferentially localized at tumor invasion margins, and is associated with activation of PI3K-Akt and TNF signaling pathways, highlighting its spatially resolved role in tumor progression. Moreover, high SUV39H1 expression defined an immunosuppressive tumor microenvironment characterized by increased infiltration of regulatory T cells and M2 macrophages, along with reduced cytotoxic CD8⁺ T cell activity, indicative of a "cold" tumor phenotype.Functional assays demonstrated that silencing SUV39H1 significantly inhibited proliferation, migration, and invasion of BC cells, confirming its causal role in driving aggressive tumor behavior.Collectively, our findings reveal that SUV39H1 orchestrates tumor stemness, immune evasion, and spatially organized tumor progression. These results not only provide mechanistic insights into bladder cancer biology but also highlight SUV39H1 as a promising therapeutic target for remodeling the tumor microenvironment and enhancing immunotherapy efficacy.