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.

The immunosuppressive landscape in tumor microenvironment.

Recent advances in cancer immunotherapy, especially immune checkpoint inhibitors (ICIs), have revolutionized the clinical outcome of many cancer patients. Despite the fact that impressive progress has been made in recent decades, the response rate remains unsatisfactory, and many patients do not benefit from ICIs. Herein, we summarized advanced studies and the latest insights on immune inhibitory factors in the tumor microenvironment. Our in-depth discussion and updated landscape of tumor immunosuppressive microenvironment may provide new strategies for reversing tumor immune evasion, enhancing the efficacy of ICIs therapy, and ultimately achieving a better clinical outcome.

Tozasertib activates anti-tumor immunity through decreasing regulatory T cells in melanoma.

Although immune checkpoint therapy has significantly improved the prognosis of patients with melanoma, urgent attention still needs to be paid to the low patient response rates and the challenges of precisely identifying patients before treatment. Therefore, it is crucial to investigate novel immunosuppressive mechanisms and targets in the tumor microenvironment in order to reverse tumor immune escape. In this study, we found that the cell cycle checkpoint Aurora kinase B (AURKB) suppressed the anti-tumor immune response, and its inhibitor, Tozasertib, effectively activated T lymphocyte cytokine release in vitro and anti-tumor immunity in vivo. Tozasertib significantly inhibited melanoma xenograft tumor growth by decreasing the number of inhibitory CD4+ Treg cells in the tumors, which, in turn, activated CD8+ T cells. Single-cell analysis revealed that AURKB suppressed anti-tumor immunity by increasing MIF-CD74/CXCR4 signaling between tumor cells and lymphocytes. Our study suggests that AURKB is a newly identified anti-tumor immunity suppressor, whose inhibitors may be developed as novel anti-tumor immunity drugs and may have synergistic anti-melanoma effects with immune checkpoint therapies.