Malignant pleural mesothelioma (MPM) is a rare aggressive tumor, mainly related to a prolonged exposure to asbestos. MPM treatment is classically based on combination of pemetrexed and platinum but its prognosis remains poor, with a median survival time estimated at 12 months. Recently, immune checkpoint blockade has shown promising early results, but only in about 20% of MPM patients. Hence, there is an urgent need for new therapeutic strategies against MPM. We have recently reported that TLR3 is highly expressed in 98% (n = 58) of MPM. We have also obtained evidence showing that not only cell lines but also primary mesothelioma cells express TLR3 and are sensitive to TLR3-triggered apoptosis.