Multi-omics profiling identifies ESM1 as a key mediator of immunoevasion through the SPP1 pathway in bladder cancer.

To investigate the predictive value of Endothelial cell-specific molecule 1 (ESM1) assay for early diagnosis and treatment of bladder cancer (BC) patients. In this study, 1558 clinical samples were included to explore the differential expression of ESM1 mRNA in BC, and in-house samples (n = 195) were collected for immunohistochemistry experiments to validate at the ESM1 protein level. ChIP-Seq, ATAC-seq, and histone modification data were integrated by Cistrome Data Browser to resolve the epigenetic regulatory mechanisms of ESM1. Single-cell sequencing analysis was used to mine the differential expression and intercellular communication of ESM1 at the cellular level. Further, GSEA and STRING were used to construct a PPI network and combined with Cytospace to mine Hub genes to reveal the immune-related pathways involved in ESM1. The potential of ESM1 in immune prediction was assessed by single sample gene set enrichment analysis. Prediction of upstream miRNAs targeting ESM1 (e.g.,miR-129-5p) and construction of regulatory networks. ESM1 protein and mRNA expression in BC tissues was significantly higher than that in normal tissues (p < 0.05), and its transcription was regulated by three major transcription factors as well as enhancers, promoters, and silencers. ESM1 was highly expressed in lymphatic endothelial cells, it participated in the SPP1 signalling pathway, which mediated immune escape and metastasis in BC. High ESM1 expression inhibited both the T-cell receptor and the Fc gamma R-mediated immune pathways and was associated with reduced tumour microenvironment scores, increased tumour purity and reduced immune cell infiltration (p < 0.05). Clinical analysis showed that ESM1 expression was significantly associated with age, ethnicity and clinical stage (p < 0.05) and was effective in differentiating cancerous tissues (AUC = 0.94). In addition, miR-129-5p expression was down-regulated in BC, with a target-regulatory relationship with ESM1 and excellent early cancer screening ability. ESM1 was specifically enriched in lymphatic endothelial cells and participated in BC progression through activation of SPP1 signalling pathway and metabolism-related signalling pathways. Overexpressed ESM1 may mediate a reduced level of immune cell infiltration in TME through immune signalling pathways. ESM1 can be used as a predictive biomarker for immune-related and clinical progression in BC.