Cuproptosis in cancer: past, present and future

Cuproptosis is a recently defined form of regulated cell death driven by disruption of intracellular copper homeostasis and is mechanistically distinct from apoptosis, ferroptosis, and other established cell-death programs. Its execution is closely linked to mitochondrial metabolism and the FDX1–protein-lipoylation machinery, together with copper-dependent aggregation of lipoylated tricarboxylic acid cycle proteins and proteotoxic stress. Loss of iron–sulfur cluster-containing proteins has also been observed as an associated feature of the defining experimental phenotype, although its precise mechanism and causal contribution to cell death remain incompletely resolved. In cancer, these mechanisms are embedded within a highly remodeled copper metabolic network involving copper uptake, intracellular trafficking, buffering, and efflux. Tumor-specific metabolic states and microenvironmental factors, including hypoxia, extracellular acidosis, inflammatory signaling, and metabolic adaptation, may therefore critically influence susceptibility or resistance to cuproptosis. Model-specific studies indicate that cuproptosis can interact with ferroptotic and immune pathways, including immunogenic cell death and cGAS–STING signaling, in defined experimental systems. These observations provide a rationale for combination strategies, but such downstream effects should not be considered universal or obligatory components of canonical cuproptosis. However, clinical translation remains constrained by the lack of validated predictive biomarkers, systemic off-target toxicity, and unfavorable pharmacokinetic properties of conventional copper ionophores. Recent advances in tumor-responsive nanomedicine and copper-based theranostic platforms may offer more precise strategies for exploiting tumor copper dependency while improving therapeutic selectivity. This review summarizes the molecular basis of cuproptosis, its regulation within the tumor microenvironment, its interactions with parallel cell-death and immune pathways, and the major opportunities and challenges for translating copper-targeted interventions into precision cancer therapy.