Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Aug. 16, 2024

Cuproptosis is a newly identified form of cell death induced by excessive copper (Cu) accumulation within cells. Mechanistically, cuproptosis results from Cu-induced aggregation dihydrolipoamide S-acetyltransferase, correlated with the mitochondrial tricarboxylic acid cycle and loss iron–sulfur cluster proteins, ultimately resulting in proteotoxic stress triggering death. Recently, has garnered significant interest tumor research due to its potential as crucial therapeutic strategy against cancer. In this review, we summarized cellular molecular mechanisms relationship other types Additionally, reviewed current drugs or strategies available induce cells, including Cu ionophores, small compounds, nanomedicine. Furthermore, targeted metabolism specific regulatory genes cancer therapy enhance sensitivity cuproptosis. Finally, discussed feasibility targeting overcome chemotherapy immunotherapy resistance suggested future directions. This study that could open new avenues for developing therapy.

Language: Английский

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Multifunctional Copper‐Phenolic Nanopills Achieve Comprehensive Polyamines Depletion to Provoke Enhanced Pyroptosis and Cuproptosis for Cancer Immunotherapy

Advanced Materials, Journal Year: 2024, Volume and Issue: 36(45)

Published: Sept. 17, 2024

Abstract The overexpression of polyamines in tumor cells contributes to the establishment immunosuppressive microenvironment and facilitates growth. Here, it have ingeniously designed multifunctional copper‐piceatannol/HA nanopills (Cu‐Pic/HA NPs) that effectively cause total intracellular depletion by inhibiting synthesis, depleting polyamines, impairing uptake, resulting enhanced pyroptosis cuproptosis, thus activating a powerful immune response achieve anti‐tumor therapy. Mitochondrial dysfunction from overall not only leads surge copper ions mitochondria, thereby causing aggregation toxic proteins induce but also triggers accumulation reactive oxygen species (ROS) within which further upregulates expression zDHHC5 zDHHC9 promote palmitoylation gasdermin D (GSDMD) GSDMD‐N, ultimately inducing pyroptosis. Then occurrence cuproptosis is conductive remodel microenvironment, responses growth metastasis. This therapeutic strategy through comprehensive provides novel template for cancer immunotherapy.

Language: Английский

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Hollow Calcium/Copper Bimetallic Amplifier for Cuproptosis/Paraptosis/Apoptosis Cancer Therapy via Cascade Reinforcement of Endoplasmic Reticulum Stress and Mitochondrial Dysfunction

ACS Nano, Journal Year: 2024, Volume and Issue: 18(43), P. 30053 - 30068

Published: Oct. 16, 2024

The endoplasmic reticulum (ER) and mitochondria are essential organelles that play crucial roles in maintaining cellular homeostasis. simultaneous induction of ER stress mitochondrial dysfunction represents a promising yet challenging strategy for cancer treatment. Herein, hollow calcium–copper bimetallic nanoplatform is developed as cascade amplifier to reinforce breast For this purpose, we report facile method preparing CaCO3 (HCC) nanoparticles by regulating the dissolution–recrystallization process amorphous CaCO3, D@HCC-CuTH meticulously fabricated sequentially coating disulfiram-loaded HCC with copper coordination polymer hyaluronan. In tumor cells, dithiocarbamate–copper complex generated situ liberated disulfiram Cu2+ inhibits ubiquitin–proteasome system, causing irreversible intracellular Ca2+ redistribution. Meanwhile, induces via triggering self-amplifying loop burst, reactive oxygen species augment. Additionally, dihydrolipoamide S-acetyltransferase oligomerization mitochondria, further exacerbating damage cuproptosis. Collectively, amplification synergistically induce cuproptosis–paraptosis–apoptosis trimodal cell death pathway, which demonstrates significant efficacy suppressing growth. This study presents paradigm synchronously inducing subcellular organelle disorders boost multimodal therapy.

Language: Английский

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Dual Metal Nanoflower Oxygen Pump Microneedles Based on Cuproptosis and STING Pathway Activation for Cancer Immunotherapy

Small, Journal Year: 2025, Volume and Issue: 21(11)

Published: Feb. 14, 2025

Abstract Immunotherapy is a promising new approach for tumor treatment. However, its clinical application hindered by insufficient immunogenicity, hypoxia, and immunosuppressive microenvironment (TME). Here, oxygen pump microneedles (OPMNs) loaded with zinc‐doped copper sulfide nanoflowers (ZCS NFs) PD‐L1 small interfering RNA (siPD‐L1) (OPMNs‐ZCS@siPD‐L1) are developed boosting immunotherapy. OPMN‐ZCS@siPD‐L1 enhances immunogenicity through ZCS NFs inducing cuproptosis, reverses TME siPD‐L1, promotes drug penetration, ameliorates hypoxia bubbles. More importantly, cuproptosis‐induced mitochondrial DNA (mtDNA) together Zn 2+ co‐activate the STING pathway, triggering robust immune response. increases sensitivity to cuproptosis induces immunogenic cell death (ICD) in vivo vitro, which significantly inhibits progression metastasis. The novel strategy of “increasing throttle” (cuproptopsis‐mediated activation & ICD effect) combined “releasing brake” (PD‐L1 inhibition improvement) provides enhancing percutaneous

Language: Английский

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Bioactive metal-based nanomedicines for boosting anti-tumor immunity: Advance, challenge, and perspective

Coordination Chemistry Reviews, Journal Year: 2024, Volume and Issue: 517, P. 215969 - 215969

Published: June 10, 2024

Language: Английский

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An antigen-capturing and lymph node-targeting nanoparticle for cancer immunotherapy

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 379, P. 993 - 1005

Published: Feb. 1, 2025

Language: Английский

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Single-atom–doped piezocatalyst induces copper-free cuproptosis in tumor therapy

Science Advances, Journal Year: 2025, Volume and Issue: 11(7)

Published: Feb. 14, 2025

Cuproptosis, a distinct cell death pathway, has been integrated into nanomedicine for disease theranostics. However, current nanosystems inducing cuproptosis rely on exogenous toxic copper ions, limiting the scope of biomaterials. Developing nanoplatforms that induce without holds substantial promise. Here, we engineered two-dimensional iron (Fe) single-atom–doped molybdenum disulfide (MoS 2 ) piezocatalyst (Fe-MoS tumor therapy. Incorporating single Fe atoms enhances MoS piezoelectric polarization via charge redistribution and modulates Mo oxidation states, enabling multifaceted enzymatic activities, including peroxidase-, glutathione oxidase–, oxidase-, catalase-like activities. Upon ultrasound stimulation, Fe-MoS nanocatalyst generates reactive oxygen species depletes synergistic piezocatalytic enzyocatalytic effects, disrupting ion homeostasis cuproptosis, concurrently triggering ferroptosis ferritinophagy, which collectively suppression. This study represents first paradigm to introduce copper-free initiating substantially advancing applications in

Language: Английский

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Zinc-copper bimetallic nanoplatforms trigger photothermal-amplified cuproptosis and cGAS-STING activation for enhancing triple-negative breast cancer immunotherapy

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 24, 2025

Triple-negative breast cancer (TNBC) is characterized by high rates of metastasis and recurrence, along with a low sensitivity to immunotherapy, resulting in paucity effective therapeutic strategies. Herein, we have developed polydopamine-coated zinc-copper bimetallic nanoplatforms (Cu-ZnO2@PDA nanoplatforms, abbreviated CZP NPs) that can efficiently induce photothermal amplified cuproptosis cGAS-STING signaling pathway activation, thereby reversing the immunosuppressive tumor microenvironment TNBC, upregulating PD-L1 expression, boosting efficacy anti-programmed death-ligand 1 antibody (αPD-L1)-based immunotherapy. Within acidic (TME), NPs spontaneously release copper zinc ions hydrogen peroxide, generating highly oxidative hydroxyl radicals downregulating iron-sulfur cluster proteins. These actions lead disruption mitochondrial integrity, DNA (mtDNA) irreversible cuproptosis. The further synergy between mtDNA potentiates activation pathway, triggering robust antitumor immune response sensitizing TNBC αPD-L1 therapy. Additionally, using an 808 nm near-infrared laser for therapy significantly augments these effects, cascade amplification against TNBC. strategic combination markedly bolsters immunity suppresses growth. Collectively, our findings present promising synergistic strategy treatment linking cuproptosis, therapy,

Language: Английский

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Self-adaptive photodynamic therapy for boosting therapeutic efficiency in tumor

Science China Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 3, 2025

Language: Английский

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The molecular mechanism and therapeutic landscape of copper and cuproptosis in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: May 8, 2025

Abstract Copper, an essential micronutrient, plays significant roles in numerous biological functions. Recent studies have identified imbalances copper homeostasis across various cancers, along with the emergence of cuproptosis, a novel copper-dependent form cell death that is crucial for tumor suppression and therapeutic resistance. As result, manipulating levels has garnered increasing interest as innovative approach to cancer therapy. In this review, we first delineate at both cellular systemic levels, clarifying copper’s protumorigenic antitumorigenic functions cancer. We then outline key milestones molecular mechanisms including mitochondria-dependent independent pathways. Next, explore cuproptosis biology, well interactions mediated by between cells immune system. also summarize emerging opportunities targeting discuss clinical associations cuproptosis-related genes. Finally, examine potential biomarkers put forward existing challenges future prospects leveraging Overall, review enhances our understanding landscape cancer, highlighting copper- or cuproptosis-based therapies treatment.

Language: Английский

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