Glutathione metabolic reprogramming by ferroptosis inducers potentiates cuproptosis and antitumor immunity in osteosarcoma.

作者：Shaoqing Xu, Ying Zhao, Jia Yao, Haoqi Chen, Jiangtao Lyu, Yina Ding, Hui Zeng, Hongyu Chen, Chuan Hu, Chengliang Zhao · 发表于：International Immunopharmacology · 年份：2026 · DOI：10.1016/j.intimp.2026.116495 · 被引用次数：1 · 研究领域：Medicine

BACKGROUND Osteosarcoma (OS) is a common malignant bone tumor that predominantly affects adolescents and is highly invasive and metastatic. Current treatment options have suboptimal efficacy, highlighting the urgent need for novel therapeutic strategies. Cuproptosis, a recently discovered form of copper-dependent cell death, has demonstrated potential in cancer therapy, yet its clinical application remains to be fully explored. Ferroptosis, another iron-dependent programmed cell death pathway, has shown efficacy against certain cancers through its induction. Recent studies suggest that ferroptosis inducers can increase cuproptosis in other cancer cells, but this synergistic effect has not been elucidated in OS. The purpose of this study was to investigate the effects of ferroptosis inducers (FINs) on cuproptosis and immunogenic cell death (ICD) induced by elesclomol‑copper premix (ES-Cu2+) in OS cells and to explore the underlying mechanisms and principles. METHODS The effects of FINs+ES-Cu2+ on cuproptotic osteosarcoma (OS) cell lines were investigated through in vitro cellular experiments. The in vivo antitumor efficacy of different drug regimens was further evaluated using an orthotopic osteosarcoma mouse model and micro-CT. RNA sequencing (RNA-Seq) was used to explore the relevant genes and pathways. RESULTS In vitro cellular experiments demonstrated that low-dose FINs can sensitize OS cells to ES-Cu2+-induced cuproptosis, increasing the expression of ICD markers. Tre...