cuproptosis
cuproptosis
Overview
Cuproptosis is a recently characterized form of regulated cell death (RCD) driven by the intracellular accumulation of copper ions, which triggers proteotoxic stress within the mitochondria. Unlike classical apoptosis or necrosis, cuproptosis is mechanistically defined by copper's direct binding to lipoylated protein components of the tricarboxylic acid (TCA) cycle — most critically dihydrolipoamide S-acetyltransferase (DLAT) — causing their aberrant aggregation and subsequent disruption of mitochondrial metabolic flux. This proteotoxic cascade blocks pyruvate entry into the TCA cycle, induces a mitochondrial crisis, and ultimately promotes cytosolic release of damaged DNA fragments, committing the cell to death. Key regulators of this process include Ferredoxin 1 (FDX1), which is required for protein lipoylation, and copper transporters such as SLC31A1 (CTR1) for copper import and ATP7A for copper efflux. Because cuproptosis operates through a mitochondria-centered mechanism that is biochemically distinct from ferroptosis, apoptosis, and pyroptosis, it has attracted substantial interest as a novel oncological target with potential to circumvent conventional therapy resistance.
The biological significance of cuproptosis extends beyond oncology. Emerging evidence implicates it in neuronal damage following copper overload, non-malignant conditions such as subarachnoid hemorrhage and preeclampsia, and fibroblast-driven fibrotic diseases including endometriosis. Its capacity to elicit immunogenic cell death — releasing damage-associated molecular patterns that stimulate dendritic cells, macrophages, and CD8+ T cells — positions cuproptosis at the intersection of metabolic disruption and antitumor immunity, making it a conceptually powerful target for combined chemo-immunotherapy strategies.
Focus of Latest Publications
Recent publications have focused on cuproptosis as both a mechanistic biomarker and a therapeutic lever in cancer and other disease settings. Several studies used multi-omics and transcriptomic analyses to characterize cuproptosis-related signatures in tumors, including thyroid cancer and pan-cancer cohorts, where cuproptosis-associated scores or gene sets were linked to molecular subtyping, prognosis, immune infiltration, and immunotherapy response. In thyroid cancer, cuproptosis-related genes were integrated with mitochondrial energy metabolism to define two molecular subtypes with distinct survival outcomes and immune microenvironments, and a simplified 3-gene prognostic model was proposed. In pan-cancer analysis, lower cuproptosis scores were associated with improved immunotherapy outcomes, greater immune infiltration and function, and higher expression of cytokines, checkpoints, and MHC molecules, suggesting that cuproptosis may help shape tumor immune landscapes.
A major theme across the recent literature is the use of cuproptosis in combination with nanomedicine and physical triggers to enhance antitumor therapy. Ultrasound-responsive copper-containing systems were reported to induce cuproptosis while also generating reactive oxygen species, supporting piezocatalytic or cascade-amplified therapy in thyroid cancer, triple-negative breast cancer, and other models. One study used a copper-coordinated covalent organic framework to enable ultrasound-controlled bioorthogonal catalysis and mitochondrial copper accumulation, thereby triggering cuproptosis alongside doxorubicin prodrug delivery. Another employed high-index facet-distorted lanthanum cuprate nanosheets to couple cuproptosis with ion overload, pyroptosis, and immunogenic cell death, while a separate hydrogen sulfide-releasing nanoplatform promoted mitochondrial copper accumulation, ROS generation, and DLAT inhibition to induce cuproptosis and remodel the tumor microenvironment.
Other studies examined cuproptosis as part of broader metabolic and immunologic reprogramming strategies. In colorectal cancer, a purpurin-copper nanoplatform combined cuproptosis with metabolic intervention and photodynamic therapy to suppress cancer stemness and convert cold tumors into T cell-inflamed phenotypes, with durable immune memory reported in rechallenge experiments. In osteosarcoma, ferroptosis inducers were investigated for their ability to potentiate cuproptosis and immunogenic cell death induced by elesclomol-copper, highlighting crosstalk between ferroptosis and cuproptosis. Across these studies, glutathione metabolism, mitochondrial dysfunction, and immune activation repeatedly emerged as key nodes linked to cuproptosis-based interventions.
Cuproptosis has also been explored outside oncology. In subarachnoid haemorrhage, brain-targeted extracellular vesicles were designed to inhibit cuproptosis as a therapeutic strategy, reflecting interest in suppressing copper-induced cell death in non-malignant injury contexts. Collectively, these publications portray cuproptosis as a biologically and therapeutically versatile process, with growing relevance to tumor metabolism, immune modulation, and precision nanotherapy.