Trace elements and tumors: homeostatic networks, molecular mechanisms and new horizons for precision intervention
8 affiliations
- 1Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan China
- 2Department of Postgraduate Students, West China Hospital, Sichuan University, Chengdu, Sichuan China
- 3West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan China
- 4Department of Hematology, Children’s Hospital of Soochow University, Suzhou, Jiangsu China
- 5Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- 6Lung Cancer Center/Lung Cancer Institute, West China Hospital, Sichuan University, Chengdu, Sichuan China
- 7Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan China
- 8Department of Urology, West China Hospital, Sichuan University, Chengdu, China
Abstract
Trace elements including iron, copper, zinc, selenium, and manganese are indispensable for life, serving as enzyme cofactors, structural components, and signaling molecules that govern energy metabolism, redox balance, and genomic stability. Their physiological functions exhibit a characteristic dose–effect biphasicity, wherein homeostatic imbalance can both safeguard health and promote malignant transformation. This review systematically delineates the complete lifecycle of these five core trace elements under physiological conditions, emphasizing their extensive functional interconnections, and elucidates how tumor cells hijack this regulatory network through an element-addiction mechanism. We detail the emerging roles of iron-dependent ferroptosis and copper-dependent cuproptosis, alongside the context-dependent regulation of apoptosis and autophagy by trace elements, revealing tumor-specific metabolic vulnerabilities. Within the tumor immune microenvironment, we examine how zinc, iron, copper, selenium, and manganese function as molecular switches: zinc and selenium generally support antitumor immunity, whereas iron and copper dysregulation drives immunosuppressive polarization; manganese additionally emerges as a cGAS-STING agonist with immunotherapeutic potential. In tumor angiogenesis and metastasis, we explore the central roles of copper and iron in extracellular matrix remodeling, epithelial-mesenchymal transition, and angiogenic signaling. Extensive clinical evidence is integrated to establish systemic and local elemental imbalances as risk biomarkers across diverse cancer types. Therapeutic strategies are categorized into traditional nutritional and pharmacological interventions, element-metabolism-based synergistic sensitization with chemotherapy, radiotherapy, and immunotherapy, and interdisciplinary engineering approaches including element-responsive nanoplatforms and synthetic biology-engineered immune cells. Throughout, we emphasize that the majority of therapeutic evidence derives from preclinical models, underscoring that rigorous foundational research must precede clinical translation. We conclude by outlining knowledge gaps and priorities for future investigation, advocating a systems biology framework that acknowledges current limitations while guiding hypothesis-driven exploration.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12943-026-02754-y.
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BibTeX
@article{zhang2026trace,
title = {{Trace elements and tumors: homeostatic networks, molecular mechanisms and new horizons for precision intervention}},
author = {Shengxin Zhang and Keqin Tan and Qin Zhang and Yuzhe Zhao and Ziyang Cheng and Xinggang Yang and Jingsi Dong and Jiaming Liu and Xuelei Ma},
journal = {Molecular Cancer},
year = {2026},
month = jul,
doi = {10.1186/s12943-026-02754-y},
url = {https://doi.org/10.1186/s12943-026-02754-y},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Trace elements and tumors: homeostatic networks, molecular mechanisms and new horizons for precision intervention
AU - Shengxin Zhang
AU - Keqin Tan
AU - Qin Zhang
AU - Yuzhe Zhao
AU - Ziyang Cheng
AU - Xinggang Yang
AU - Jingsi Dong
AU - Jiaming Liu
AU - Xuelei Ma
PY - 2026
DA - 2026/07/30
JO - Molecular Cancer
DO - 10.1186/s12943-026-02754-y
UR - https://doi.org/10.1186/s12943-026-02754-y
AB - Trace elements including iron, copper, zinc, selenium, and manganese are indispensable for life, serving as enzyme cofactors, structural components, and signaling molecules that govern energy metabolism, redox balance, and genomic stability. Their physiological functions exhibit a characteristic dose–effect biphasicity, wherein homeostatic imbalance can both safeguard health and promote malignant transformation. This review systematically delineates the complete lifecycle of these five core trace elements under physiological conditions, emphasizing their extensive functional interconnections, and elucidates how tumor cells hijack this regulatory network through an element-addiction mechanism. We detail the emerging roles of iron-dependent ferroptosis and copper-dependent cuproptosis, alongside the context-dependent regulation of apoptosis and autophagy by trace elements, revealing tumor-specific metabolic vulnerabilities. Within the tumor immune microenvironment, we examine how zinc, iron, copper, selenium, and manganese function as molecular switches: zinc and selenium generally support antitumor immunity, whereas iron and copper dysregulation drives immunosuppressive polarization; manganese additionally emerges as a cGAS-STING agonist with immunotherapeutic potential. In tumor angiogenesis and metastasis, we explore the central roles of copper and iron in extracellular matrix remodeling, epithelial-mesenchymal transition, and angiogenic signaling. Extensive clinical evidence is integrated to establish systemic and local elemental imbalances as risk biomarkers across diverse cancer types. Therapeutic strategies are categorized into traditional nutritional and pharmacological interventions, element-metabolism-based synergistic sensitization with chemotherapy, radiotherapy, and immunotherapy, and interdisciplinary engineering approaches including element-responsive nanoplatforms and synthetic biology-engineered immune cells. Throughout, we emphasize that the majority of therapeutic evidence derives from preclinical models, underscoring that rigorous foundational research must precede clinical translation. We conclude by outlining knowledge gaps and priorities for future investigation, advocating a systems biology framework that acknowledges current limitations while guiding hypothesis-driven exploration. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12943-026-02754-y.
SN - 1476-4598
ER -