Metal Ion-Mediated Regulation of Cell Fate: A Novel Strategy for Synergy with Radiotherapy and Immunotherapy

Metal ions are indispensable for living organisms, participating in essential physiological processes. However, their dysregulated accumulation can trigger cell death and metal overload. The recent discovery of novel regulated cell death modalities, such as cuproptosis and ferroptosis, has significantly advanced the understanding of metal ions in cell fate and immune regulation. This review systematically elucidates the molecular mechanisms underlying metal ion-induced cell death, encompassing oxidative stress, mitochondrial dysfunction, DNA damage, and epigenetic modifications. It further classifies and discusses the hallmarks of various programmed and non-programmed cell death pathways, emphasizing the pivotal role of metal ions in anti-tumor immunity. Moreover, we highlight an emerging therapeutic approach-metal ion-based immunotherapy, which represents a compelling strategy when combined with radiotherapy to amplify therapeutic outcomes. This combined modality holds significant promise for overcoming radiotherapy resistance and expanding its abscopal effects. Finally, current challenges and future research directions in the field of metal immunity are outlined to facilitate the translational application of metal ions in disease therapy and immune modulation.