Abstract
BACKGROUND: Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) regulates extracellular nucleotide metabolism and immune suppression. While ENPP1 is implicated in tumor progression and immune evasion in various cancers, its role in bladder cancer (BC) remains unclear. Understanding its impact on tumor malignancy and immune escape is essential for improving treatment strategies. METHODS: We analyzed ENPP1 expression in BC tissues and TCGA–BLCA datasets, correlating it with clinicopathological features, prognosis, and immune infiltration. Functional assays, including CCK–8, colony formation, invasion, wound healing, and apoptosis assays, were conducted. CD8⁺ T cell recruitment and cytotoxicity were evaluated through co–culture and cytokine assays. ENPP1–mediated suppression of cGAS–STING signaling was assessed via Western blot and IFN–β quantification. Chromatin immunoprecipitation (ChIP) and dual–luciferase reporter assays confirmed JUN as a transcriptional activator of ENPP1. In vivo models assessed the therapeutic potential of ENPP1 knockdown combined with PD–L1 blockade. RESULTS: ENPP1 was upregulated in advanced BC and correlated with poor survival outcomes. It promoted tumor proliferation, migration, and invasion, while inhibiting apoptosis and CD8⁺ T cell infiltration via CCL5 and CXCL10 downregulation. Mechanistically, ENPP1 suppressed cGAS-STING activation, facilitating immune evasion. JUN directly activated ENPP1 transcription, forming a JUN-ENPP1-cGAS-STING axis that sustains tumor progression and immune suppression. In vivo, ENPP1 knockdown enhanced PD-L1 blockade efficacy, reducing tumor growth and increasing CD8⁺ T cell infiltration. CONCLUSIONS: ENPP1 promotes BC malignancy and immune evasion, and targeting the JUN–ENPP1–cGAS–STING axis may enhance anti–tumor immunity and immunotherapy efficacy in BC patients. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-07275-8.