Targeting mir130b-IL-33-PD-L1 axis effectively inhibits esophageal squamous carcinoma progression.

We used an integrated approach combining molecular biology techniques, animal experiments, and clinical samples to elucidate the mechanistic basis of interleukin-33 (IL-33)-induced programmed death-ligand 1 (PD-L1) upregulation and its role in squamous cell carcinoma (ESCC) progression. Multi-omics analyses and clinical datasets identified that increased expression of IL-33 and its receptor in tumor tissues correlated with advanced stage and poor prognosis. IL-33 expression was associated with enhanced migration, invasion, and proliferation of tumor cells, and these effects were partly reversed by PD-L1 inhibition. Real-time PCR (qPCR) and functional assays in ESCC cell lines demonstrated that microRNA-130b-3p suppressed tumor progression by downregulating RUNX3, a transcriptional activator of IL-33. Dual-luciferase reporter assays confirmed direct targeting of RUNX3 by microRNA-130b-3p In vivo, microRNA-130b-3p overexpression reduced tumor growth in xenograft models and decreased levels of IL-33, PD-L1, and proliferation markers. Conversely, microRNA knockdown promoted tumor progression. Immunohistochemical analysis showed co-expression of IL-33 and PD-L1 in tumor cells, and PD-L1 blockade diminished IL-33-induced anti-apoptotic effects. Data integration revealed significant co-expression of IL-33 and PD-L1 across cancer types, suggesting a broader regulatory role. These findings establish a mechanistic link between microRNA-130b-3p and immune checkpoint activation through IL-33 signaling. The study identifies IL-33 as an independent prognostic marker and a key driver of PD-L1 expression, providing a basis for dual-targeted therapeutic strategies.