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.

Key Publications

NEWJun Deciphering the interplay between cuproptosis and mitochondrial energy metabolism in thyroid cancer: a multi-omics study for molecular subtyping, prognosis, and tumor microenvironment characterization. (Molecular and cellular biochemistry, 2026, PMID 42319714): "The interaction between cuproptosis, a novel copper-dependent form of cell death, and mitochondrial energy metabolism, a key regulator of cellular bioenergetics, may influence tumor behavior, yet its role in THCA is not fully elucidated."
NEWJun A sonopiezoresponsive covalent organic framework-based smart nanoreactor orchestrates in situ bioorthogonal chemistry and cuproptosis for enhanced tumor therapy. (Acta biomaterialia, 2026, PMID 42288303): "to enhance the antitumor efficacy of PCT through the combination of cuproptosis and bioorthogonal catalysis."
May Cuproptosis as a novel predictor of immunotherapy response and shapes the immune landscape in pan-cancer analysis. (Discover oncology, 2026, PMID 42065821): "As a form of recently defined regulated cell death (RCD), cuproptosis is driven by copper-dependent proteotoxic stress in mitochondria tricarboxylic acid cycle (TCA cycle), exerting a sophisticated role in antitumor immunity, yet remains poorly understood."
Apr High-Index Facet-Distorted Lanthanum Cuprate for Ultrasound-Triggered Cuproptosis and Cascade-Amplified Antitumor Therapy. (Small (Weinheim an der Bergstrasse, Germany), 2026, PMID 42023556): "Enhanced Cu2+/Cu+ conversion under US triggers cuproptosis, and La3+ released from LCO acted as super calcium, enhancing mitochondrial Ca2+ uptake and thereby inducing ions overload."
May Glutathione metabolic reprogramming by ferroptosis inducers potentiates cuproptosis and antitumor immunity in osteosarcoma. (International immunopharmacology, 2026, PMID 41855775): "Cuproptosis, a recently discovered form of copper-dependent cell death, has demonstrated potential in cancer therapy, yet its clinical application remains to be fully explored."
May Cascade-responsive hydrogen sulfide-releasing nanoplatform for synergistic tumor photothermal-immunotherapy. (Journal of colloid and interface science, 2026, PMID 41605106): "DCTH was composed of a Cu2O core serving as a Cu+ source and near-infrared (NIR) photothermal agent, a triphenylphosphine-functionalized chitosan (TPP-CS) layer for mitochondrial targeting and Cu+ stabilization, a GSH-responsive dendritic mesoporous organosilica (DMOS) shell for controlled co-release of H2S/Cu+, and an outer hyaluronic acid (HA) shell facilitating tumor accumulation via CD44-mediated endocytosis."
May Nano-purpurin-Cu delivery via TPGS-induced macropinocytosis enables cuproptosis/metabolic synergy to ablate cancer stemness and Boost immunotherapy in colorectal cancer. (Biomaterials, 2026, PMID 41330333): "Furthermore, copper ion-driven cuproptosis synergizes with chlorin e6 (Ce6)-generated reactive oxygen species (ROS) to ablate cancer stemness, effecting robust conversion of immunologically cold tumors to T cell-inflamed hot phenotypes."
Apr Brain-targeted extracellular vesicles for anti-cuproptosis therapy in subarachnoid haemorrhage. (Stroke and vascular neurology, 2026, PMID 40953925): "Cuproptosis is a copper-induced cell death that regulates lipoylated tricarboxylic acid cycle proteins."