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

Liu et al. Cell Communication and Signaling https://doi.org/10.1186/s12964-024-01759-8 (2024) 22:378 Cell Communication and Signaling Open Access RESEARCH Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1 Wuyi Liu1†, Huyue Zhou1†, Wenjing Lai1, Changpeng Hu1, Qiaoling Wang1, Chengsha Yuan1, Chunmei Luo1, Mengmeng Yang1, Min Hu1, Rong Zhang1* and Guobing Li1* 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. Keywords Artesunate, Melanoma, Ferroptosis, CD8+ T cell, Ido1 Introduction Melanoma, an aggressive malignancy originating from pigment-producing melanocytes, is primarily localized at the epidermal-dermal junction in human skin, contributing significantly to skin cancer-related fatalities [1]. Although surgery can often cure primary melanomas in the early stages, approximately 20% of patients still advance to metastatic disease [2]. Despite substantial achievements in current therapeutic strategies such † Wuyi Liu and Huyue Zhou contributed equally to this work. *Correspondence: Rong Zhang Guobing Li 1 Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing 400037, China as targeted therapy and immunotherapies, many patients fail to benefit due to low response rates, extensive adverse events and drug resistance. Thus, the development of novel therapeutic drugs and clarification of their antimelanoma mechanism are imperative to improve the clinical outcomes of melanoma patients. Ferroptosis is a newly discovered form of non-apoptotic cell death characterized by iron-dependent lipid peroxidation [3]. The accumulation of reactive oxygen species (ROS) and free iron leads to lipid peroxidation, which ultimately triggers ferroptosis [4]. In the pursuit of proliferation and progression, cancer cells harbor higher levels of catalytic Fe2+ than normal cells, suggesting the induction of ferroptosis may selectively inhibit tumor proliferation and progression [4]. Recent studies have increasingly demonstrated that ferroptosis exerts inhibitory effects on cancer cell growth across various © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.To view a copy of this licence, visit http:// creativecommons.org/licenses/by-nc-nd/4.0/. Liu et al. Cell Communication and Signaling (2024) 22:378 malignancies [5, 6]. Therefore, targeting ferroptosis to eliminate tumors is considered a promising strategy for cancer therapy. Traditional Chinese medicine (TCM) have a long history of clinical practice, and in recent years, they have garnered increased attention for their promising anticancer potential. In clinical, many anticancer drugs are obtained from natural products or their derivatives [7]. Artesunate (ART), a water-soluble semi-synthetic derivative of artemisinin, was first discovered by Youyou Tu in 1972 from Artemisia annuaL. Beyond its traditional anti-malarial effect, recent studies have unveiled numerous bioactivities of ART, including anti-inflammatory, anti-viral, especially anticancer effects both in vitro and in vivo [8–11]. Moreover, ART has demonstrated robust antitumor effects in select types of cancers with minimal toxicity towards normal cells, which has also been proved in clinical trials [12–14]. However, studies investigating the effects of ART on melanoma are scarce, and the underlying molecular mechanisms of its anticancer effects remain unclear. Recently, ART was found to regulate immune cells and promote antitumor immunity [15, 16]. Considering the importance of immune-evasion in melanoma therapy and the central contribution of CD8+ T cells to the anti-tumor immune response, it is essential to explore whether ART affects CD8+ T cell function and remodels the tumor microenvironment (TME). Indoleamine2,3dioxygenase 1 (Ido1), a cytosolic heme-containing enzyme, catabolizes the degradation of tryptophan (Trp) and the production of Kynurenine (Kyn). Ido1 is frequently overexpressed in various cancer types, exhibiting an inverse correlation with the overall survival of cancer patients [17–20]. Ido1 promotes the immunosuppressive regulatory T cells (Tregs) and suppresses CD8+ T effector cells, facilitating an immunosuppressive microenvironment [21–23]. Thus, Ido1 emerges as an attractive target for anticancer drug development [24]. Recent findings indicate that Ido1 inhibitors possess anticancer effects in preclinical models, clinical trials, thus, the clinical application of Ido1 inhibitors would enhance the outcomes of cancer treatment [25, 26]. In this study, we found that ART effectively inhibits the proliferation of multiple melanoma cells and induces ferroptosis by elevating ROS and MDA production, along with lipid peroxidation. Mechanistically, ART triggers ferroptosis in melanoma cells by directly targeting Ido1, consequently suppressing Hic1-mediated transcription suppression of Hmox1. Moreover, ART also actives CD8+ T cells by targeting Ido1, thereby increasing tryptophan, decreasing NFATc1, inhibiting the transcription of PD1 and finally enhancing effector function of CD8+ T cells. Our s (...truncated)