Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1

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.