AbstractBackgroundSynovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS.MethodsHuman SS cell lines were continuously irradiated with BL using light‐emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs.ResultsBL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N‐acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3‐methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model.ConclusionTaken together, our results revealed that BL induced apoptosis via the ROS‐mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS.