Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1
Wuyi Liu, Huyue Zhou, Wenjing Lai, Changpeng� Hu, Qiaoling Wang, Chengsha Yuan, Chunmei Luo, Mengmeng Yang, Min Hu, Rong Zhang, Guobing� Li
Abstract
Artesunate (ART), a natural product isolated from traditional Chinese plant Artemisia annua , has not been extensively explored for its anti-melanoma properties. In our study, we found that ART inhibited melanoma cell proliferation and induced melanoma cell ferroptosis. Mechanistic study revealed that ART directly targets Ido1, thereby suppressing Hic1-mediated transcription suppression of Hmox1, resulting in melanoma cell ferroptosis. In CD8 + T cells, ART does not cause cell ferroptosis due to the low expression of Hmox1. It also targets Ido1, elevating tryptophan levels, which inhibits NFATc1-mediated PD1 transcription, consequently activating CD8 + T cells. Our study uncovered a potent and synergistic anti-melanoma efficacy arising from ART-induced melanoma cell ferroptosis and concurrently enhancing CD8 + T cell-mediated immune response both in vivo and in vitro through directly targeting Ido1. Our study provides a novel mechanistic basis for the utilization of ART as an Ido1 inhibitor and application in clinical melanoma treatment.