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Background Malignant pleural mesothelioma (MPM) is a particularly fatal cancer with a median survival of less than one year. The value of single-agent checkpoint inhibitors is still obscure in MPM. We aim to reveal CUL4B prognostic role and immune infiltrates in MPM patients. Methods CUL4B expression profile and clinical information of malignant pleura mesothelioma individuals were collected from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) dataset. Quantitative real-time PCR (qRT-PCR) analysis measured CUL4B mRNA expression in epithelioid, biphasic, sarcomatoid, and normal pleural cell lines. Results CUL4B expression elevated in MPM and had a high diagnostic value with AUC = 0.772. Additionally, our results showed that CUL4B high expression significantly correlated with poorer outcomes in MPM. Moreover, GSEA revealed 15 KEGG pathways enriched in the CUL4B high-expression group, and 22 were exhibited in the CUL4B low-expression group. Otherwise, our results showed that CUL4B was relevant to Wnt antagonistic factors (BARX2), Insulin-like growth factor binding protein 3 (IGFBP3), and Phosphatase and tensin homolog (PTEN). In addition, our results revealed that CUL4B expression was positively linked with four types of immune cells, whereas CUL4B expression was negatively linked with three types of immune cells. Additionally, our results showed that CUL4B expression regulates T helper cells, Tcm, and Th2 cells infiltration MPM microenvironment. Finally, our results identified CUL4B high expression in MPM cell line NCI-H2052 (epithelioid), MSTO-211H (biphasic), and NCI-H28 (sarcomatoid). Conclusion CUL4B is a valuable prognostic biomarker and a critical immune cell infiltration regulator in MPM.

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