NU-1025 Modulates Immunogenic Cell Death in Bladder Cancer: A Multi-omics Insight

Immune checkpoint blockade has shown limited efficacy in bladder cancer, underscoring the need for therapeutic strategies that enhance tumor immunogenicity. Immunogenic cell death (ICD) can stimulate adaptive immunity and remodel the tumor microenvironment, yet its comprehensive landscape and druggable potential in bladder cancer remain unexplored. Here, we performed integrative bioinformatics analysis of transcriptomic data from TCGA and GEO bladder cancer cohorts to characterize ICD-associated subtypes, construct a prognostic risk model, and analyze immune infiltration. Connectivity Map (CMap) database and the XSum algorithm were employed for computational drug screening. Molecular docking was used to predict interactions between candidate compounds and immune checkpoint proteins. In silico ADMET and toxicology profiles were evaluated. The clinical relevance was assessed through independent CT urography imaging and PD-L1 immunohistochemistry data. Two ICD molecular subtypes were identified with distinct prognostic and microenvironment features. An eight-gene ICD risk model was established and validated, effectively stratifying patients into high- and low-risk groups with differential survival, immune cell infiltration, and tumor mutational burden. Through computational screening, NU-1025 was nominated as a top candidate capable of reversing the high-risk gene expression pattern. In silico profiling indicated favorable drug-like properties and low toxicity risk. Clinical data analysis revealed that high-grade bladder tumors frequently exhibit low PD-L1 expression, aligning with the predicted need for ICD-inducing agents. Overall, this research decodes the ICD landscape in bladder cancer and, via a computational drug repurposing pipeline, nominates NU-1025 as a novel candidate with predicted ICD-inducing and/or immune checkpoint modulatory activity.