The Cancer Metallome Continuum: A Framework for Understanding Metal Dysregulation from Carcinogenesis to Therapeutic Resistance

Abstract Metals and metalloids play essential roles in cancer biology, influencing redox balance, epigenetic regulation, immune responses, and cell death throughout tumour development, progression, and resistance to therapy. Despite this broad biological relevance, the systematic clinical integration of metallomics into oncology remains in its early stages. This review introduces the Cancer Metallome Continuum (CMC), a framework illustrating how metallomic reprogramming evolves from cancer initiation through progression to therapy-resistant states, and evaluates the analytical, systems-level, and translational approaches needed to test it. In early stages of cancer, toxic metals such as As, Cd, hexavalent chromium [Cr(VI)], and Ni induce oxidative stress, epigenetic modifications, and DNA repair defects. During progression, dyshomeostasis of essential metals creates tumour-specific dependencies. For example, Fe accumulation can support tumour growth, while tumour cells concurrently engage anti-ferroptotic programs; Cu contributes to angiogenesis and kinase signalling, and Zn transporter networks regulate apoptosis and immune responses. Under treatment pressure, tumours adapt by rewiring metal transporters, upregulating metallothionein buffering, and suppressing metal-dependent cell death pathways, including ferroptosis and cuproptosis. Translational advances include selenium-based prognostic panels with replicated evidence in breast cancer (SCAN-B) and colorectal cancer (CORSA), Cu-chelation trials, and spatially resolved metallodrug imaging. The strongest human evidence currently supports Se-based prognostic panels (replicated across breast and colorectal cancer cohorts) and the feasibility of biomarker-guided Cu depletion (a Phase II single-arm trial), while spatial integration and artificial intelligence/machine learning (AI/ML) applications remain at the proof-of-concept or emerging stages. Clinical translation will require tighter control of preanalytical variability, prospective multicentre validation, and standardized reporting.