cuproptosis

Overview

Cuproptosis is a form of regulated cell death driven by intracellular copper accumulation acting on the mitochondria. Its defining mechanism is unusual among cell-death pathways in that it has no dedicated executioner protein: copper binds directly to the lipoyl moieties of tricarboxylic acid (TCA) cycle enzymes, most critically dihydrolipoamide S-acetyltransferase (DLAT), causing them to aggregate. The aggregated, lipoylated proteins are themselves the toxic species, and their accumulation coincides with destabilization of iron–sulfur cluster proteins, blocking pyruvate entry into the TCA cycle and producing a proteotoxic mitochondrial crisis that kills the cell. Ferredoxin 1 (FDX1) (FDX1) is required at two points — reducing Cu²⁺ to the more reactive Cu⁺ and supporting protein lipoylation — which makes it the principal determinant of susceptibility, alongside the copper transporters SLC31A1 (CTR1) for import and ATP7A for efflux.

Because the death depends on lipoylated TCA enzymes being present and active, it selectively kills cells that respire: tumors relying on oxidative phosphorylation are sensitive, while glycolytic cells largely resist, and the same lesion can be induced experimentally with copper ionophores such as elesclomol that carry copper past normal import controls. This metabolic dependency is what distinguishes cuproptosis mechanistically from ferroptosis, apoptosis and pyroptosis, and what makes it attractive as a way to attack tumors selected by metabolic state rather than by mutation, potentially circumventing conventional resistance.

Its significance extends beyond oncology. copper overload injures neurons and underlies Wilson disease, in which failure of hepatic copper export produces liver and neurological damage, and cuproptosis has been implicated in subarachnoid hemorrhage, preeclampsia and fibroblast-driven fibrotic disease including endometriosis. Its capacity to elicit immunogenic cell death — releasing damage-associated molecular patterns that stimulate dendritic cells, macrophages and CD8+ T cells — places it at the intersection of metabolic disruption and antitumor immunity, and is the rationale for combining copper-directed agents with immunotherapy.

Recent Publications Summary

Recent studies have positioned cuproptosis as both a therapeutic mechanism and a biomarker across diverse cancer contexts. Multiple nanoparticle-based platforms were designed to induce copper-dependent cell death in tumors while simultaneously enhancing radiotherapy, phototherapy, or immunotherapy. copper carbonate nanoparticles established a self-reinforcing cuproptosis-radiotherapy loop by remodelling the tumor microenvironment, downregulating CDK1, causing G2/M arrest, and increasing radiosensitivity; radiotherapy also suppressed ATP7A, reinforcing intracellular copper retention and further promoting cuproptosis 42587511Aug. In triple-negative breast cancer, a copper-doped hafnium oxide nanoradiosensitizer combined with brachytherapy triggered radiation-responsive Cu+ release, intracellular copper overload, cuproptosis, cGAS-STING activation, and immunogenic cell death, leading to primary tumor suppression, reduced metastasis, and an abscopal effect in a radioresistant model 42584274Aug. Similar synergistic approaches were reported for ultrasound-triggered systems, including high-index facet-distorted lanthanum cuprate nanosheets that coupled cuproptosis with ion overload, pyroptosis, and immunogenic cell death, producing strong tumor inhibition 42023556Apr, and photothermal pulse output nanomachines that supported photothermal therapy together with enhanced cuproptosis 42378513Jun.

Cuproptosis was also integrated into localized drug-delivery and immunomodulatory strategies. An injectable pH-responsive GelMA hydrogel co-delivering sunitinib and copper oxide nanoparticles released CuO nanoparticles and Cu2+ in the acidic tumor microenvironment, inducing mitochondrial proteotoxic stress, depletion of iron-sulfur cluster proteins, reactive oxygen species generation, and damage-associated molecular pattern release alongside anti-angiogenic therapy in clear cell renal cell carcinoma 42392517Jul. A cascade-responsive nanoplatform that co-released H2S and Cu+ promoted intracellular acidification, inhibited copper efflux via ATP7A downregulation, increased mitochondrial copper accumulation, generated ROS, and induced cuproptosis as part of a broader photothermal-immunotherapeutic strategy 41605106Jan. In colorectal cancer, a purpurin-copper nanoplatform used TPGS-induced macropinocytosis to increase intracellular delivery, reprogrammed glutamine metabolism, and combined cuproptosis with photodynamic therapy to ablate cancer stemness and convert immunologically cold tumors into T cell-inflamed phenotypes 41330333Dec. Another ultrasound-controlled nanoreactor based on copper-coordinated covalent organic frameworks combined cuproptosis with bioorthogonal catalysis to enhance piezocatalytic tumor therapy 42288303Jun.

Beyond direct therapeutics, several publications examined how cuproptosis relates to tumor biology, immune context, and prognosis. A pan-cancer analysis developed a cuproptosis score associated with immune landscape features and immunotherapy response, with cuproptosis-low patients tending to have better outcomes, higher immune infiltration, and greater expression of cytokines, checkpoints, and MHC molecules; immune cells also appeared more cuproptosis-prone than tumor cells in spatial analyses 42065821May. In thyroid cancer, multi-omics analysis of cuproptosis- and mitochondrial energy metabolism-related genes identified molecular subtypes with distinct survival outcomes and immune microenvironment characteristics 42319714Jun. In osteosarcoma, ferroptosis inducers were reported to potentiate cuproptosis and immunogenic cell death induced by elesclomol-copper, linking glutathione metabolic reprogramming with enhanced antitumor immunity 41855775Mar. Outside oncology, cuproptosis inhibition was explored as a treatment strategy in subarachnoid haemorrhage through brain-targeted extracellular vesicle delivery of siRNA 40953925Sep.

What Changes, What Holds

1. Cuproptosis can be coupled to radiation and imaging-delivered therapies to amplify tumor killing
NEW DIRECTION copper-directed platforms are being used less as standalone death inducers and more as radiosensitizing or multimodal effectors, with the added consequence that cuproptosis now sits inside broader tumor-microenvironment and immune-activation strategies 42587511Aug42584274Aug. This extends the baseline’s therapeutic promise into combination engineering, including cGAS-STING activation, immunogenic cell death, and abscopal activity, but it does not displace the established mitochondrial mechanism of cuproptosis.

2. Local delivery systems can trigger cuproptosis while also suppressing angiogenesis, phototherapy resistance, and immune coldness
REINFORCES Injectable hydrogels and cascade-responsive nanoplatforms sharpen the baseline’s idea that intracellular copper overload is exploitable therapeutically, adding practical delivery routes and combination logic rather than new biology 42392517Jul41605106Jan. The colorectal and piezocatalytic systems likewise reinforce cuproptosis as a modifiable anticancer mechanism, with added effects on glutamine metabolism and stemness, but these are still applications of the same established copper-dependent death program.

3. Cuproptosis is emerging as a prognostic and immunologic biomarker, and its inhibition may be useful outside cancer
NEW DIRECTION Pan-cancer scoring and subtype analyses move cuproptosis beyond a death mechanism into a stratification tool linked to immune landscape and immunotherapy response, which the Overview did not yet cover 42065821May42319714Jun. The osteosarcoma and subarachnoid haemorrhage findings also broaden the field in opposite directions: one suggests potentiating cuproptosis can augment antitumor immunity, while the other suggests suppressing it may be beneficial in acute brain injury 41855775Mar40953925Sep.

Overview update candidates: cuproptosis-based prognostic/immune biomarkers; potential therapeutic inhibition in subarachnoid haemorrhage.