Trace elements and tumors: homeostatic networks, molecular mechanisms and new horizons for precision intervention.

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.