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Simple Summary: Malignant pleural mesothelioma (MPM) is characterized by the lack of effective long-term treatments and highly prevalent drug resistance. The paucity of potential therapeutic targets has led to dismal prognosis. We have examined the functional role of the signal transducer and activator of transcription 3 (STAT3) transcription factor in MPM. Even though highly specific STAT3 inhibitors have not yet come to fruition, we performed experiments targeting STAT3 expression and subsequently supported these experiments with small molecule drugs that were previously validated to target STAT3-dependent activation mechanisms. These drugs are United States Food and Drug Administration (FDA)-approved and showed efficacy in preclinical models of MPM at concentrations that can safely be achieved in humans. We also identified genes that strongly support the essential role of STAT3 in cell growth and are consistent with a role of STAT3 in immune suppression. Overall, the results establish a central role for STAT3 in tumor growth and encourage further expedient development of STAT3 pathway inhibitors for clinical use. Malignant pleural mesothelioma (MPM) is an aggressive cancer defined by loss-of-function mutations with few therapeutic options. We examined the contribution of the transcription factor Signal transducer and activator of transcription 3 (STAT3) to cell growth and gene expression in preclinical models of MPM. STAT3 is activated in a variety of tumors and is thought to be required for the maintenance of cancer stem cells. Targeting STAT3 using specific small hairpin RNAs (shRNAs) or with the pharmacologic inhibitors atovaquone or pyrimethamine efficiently reduced cell growth in established cell lines and primary-derived lines while showing minimal effects in nontransformed LP9 mesothelial cells. Moreover, atovaquone significantly reduced viability and tumor growth in microfluidic cultures of primary MPM as well as in an in vivo xenotransplant model. Biological changes were linked to modulation of gene expression associated with STAT3 signaling, including cell cycle progression and altered p53 response. Reflecting the role of STAT3 in inducing localized immune suppression, using both atovaquone and pyrimethamine resulted in the modulation of immunoregulatory genes predicted to enhance an immune response, including upregulation of ICOSLG (Inducible T-Cell Costimulator Ligand or B7H2). Thus, our data strongly support a role for STAT3 inhibitors as anti-MPM therapeutics. [ABSTRACT FROM AUTHOR]