Pleural mesothelioma (PM) urgently requires effective treatments. This study aimed to identify potential therapies using a drug repurposing strategy in the context of the molecular heterogeneity of PM. We performed a multiomics study of a large cohort of patient-derived primary PM cell lines (n=58) and conducted a multi-step pharmacological study starting with a large-scale drug screen with 1327 compounds using 11 cell lines to select drugs of interest. Integrated multiomics analysis demonstrated that the molecular landscape of the cell line cohort recapitulates the main findings in tumors and revealed important features of PM. Large-scale drug screening identified 233 active compounds belonging to recurrent therapeutic classes. Subsequent validation of 35 compounds highlighted a subset of 12 compounds performing better than standard chemotherapy, including entinostat and fluvastatin, with therapeutic activity related to molecular sarcomatoid phenotype, BAP1 mutation, and YAP/TAZ activity. Importantly, both compounds displayed the same efficacy in 2D and 3D culture models, and a single treatment with entinostat improved survival in an immunocompetent mouse model compared with fluvastatin and standard cisplatin-pemetrexed chemotherapy, which showed similar anti-tumor effects. Strikingly, entinostat improved the efficacy of immunotherapy based on anti-PD1 antibody. Combination of entinostat with anti-PD1 even eradicated tumors in several mice and immunized them against re-transplantation of tumor cells. Overall, the drug sensitivity data provided by this study represents a resource to facilitate future clinical investigations to improve treatment of PM.