Cuproptosis in the tumor microenvironment: metabolic–immune regulatory mechanisms and therapeutic potential

Copper is an essential trace element involved in mitochondrial respiration, redox homeostasis, and numerous enzymatic reactions. Recent studies across multiple cancers have reported changes in tissue copper levels, circulating copper-related indicators, and networks governing copper uptake, transport, and efflux. The discovery of cuproptosis, a copper-dependent form of regulated cell death driven by mitochondrial metabolism, further linked copper homeostasis to cell death regulation. Its key molecular features include copper binding to lipoylated tricarboxylic acid (TCA) cycle proteins, aggregation of lipoylated proteins, loss of iron–sulfur cluster proteins, and proteotoxic stress. Within the tumor microenvironment, heterogeneity in copper uptake and export, TCA cycle activity, ferredoxin 1 (FDX1) function, protein lipoylation, and redox buffering collectively shapes cuproptosis susceptibility, which cannot be reliably predicted by tissue copper content or a single metabolic phenotype alone. Preclinical studies of cuproptosis-inducing interventions have also reported damage-associated molecular pattern release, dendritic cell maturation, CD8 + T-cell infiltration, and myeloid-cell remodeling; however, these effects often coexist with oxidative stress, other forms of cell death, or multimodal therapies, and their mechanistic specificity for cuproptosis remains variable. This review examines cuproptosis from a tumor microenvironment perspective by integrating clinical and molecular evidence of altered copper homeostasis, defining the boundaries among copper dysregulation, general copper-related cytotoxicity, and cuproptosis, and discussing how copper availability, the FDX1–protein lipoylation axis, mitochondrial metabolic states, and microenvironmental adaptation influence susceptibility. We further evaluate immune effects according to the strength of available evidence and summarize therapeutic strategies involving copper ionophores, copper-homeostasis modulation, metabolic sensitization, nanodelivery, and combination immunotherapy. This framework clarifies the relationships among copper homeostasis, tumor metabolism, cuproptosis susceptibility, and immune responses, while highlighting priorities for mechanistic investigation and therapeutic translation.