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

## TL;DR

This paper explores how metal ions can regulate cell death and boost cancer treatments like radiotherapy and immunotherapy.

## Contribution

The paper introduces metal ion-mediated regulation as a novel strategy to enhance radiotherapy and immunotherapy synergy.

## Key findings

- Metal ions influence cell death and anti-tumor immunity through mechanisms like oxidative stress and DNA damage.
- Combining metal ion-based therapies with radiotherapy can overcome resistance and enhance therapeutic outcomes.
- Emerging strategies like cuproptosis and ferroptosis highlight metal ions' role in programmed cell death and immune regulation.

## Abstract

Radiotherapy and immunotherapy are key cancer treatments, yet both face limitations. Metal ions, beyond their traditional roles, are now recognized as important regulators of cell death and immune responses. This review explains how metal ions influence cell fate and anti-tumor immunity, and explores their potential to enhance radiotherapy by boosting immune effects and overcoming resistance. By connecting these mechanisms, our work provides a clear framework for developing new combined therapies, offering valuable insights for researchers and clinicians in oncology, immunology, and related fields.

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.