Copper‐Based Composites Nanoparticles Improve Triple‐Negative Breast Cancer Treatment with Induction of Apoptosis‐Cuproptosis and Immune Activation

Advanced Healthcare Materials, Год журнала: 2024, Номер 13(28)

Опубликована: Июль 12, 2024

The synergistic effect of apoptosis and cuproptosis, along with the activation immune system, presents a promising approach to enhance efficacy against triple-negative breast cancer (TNBC). Here, two prodrugs are synthesized: reactive oxygen species (ROS)-responsive prodrug PEG-TK-DOX glutathione (GSH)-responsive PEG-DTPA-SS-CPT. These self-assembled chelated Cu2+ prepare nanoparticle PCD@Cu that simultaneously loaded doxorubicin (DOX), camptothecin (CPT), Cu2+. elevated levels ROS GSH in TNBC cells disrupted structure, leading release Cu+, DOX, CPT depletion GSH. DOX triggered immunogenic cell death (ICD) cells. Simultaneously, downregulated expression copper transporting ATPase 2 (ATP7B), causing significant accumulation ions This further induced aggregation lipoylated dihydrolipoamide S-acetyltransferase (DLAT) downregulation iron-sulfur (Fe-S) cluster proteins, ultimately cuproptosis ICD TNBC. In vitro vivo experiments confirmed activated demonstrating strong anti-tumor capabilities. Moreover, exhibited an excellent biosafety profile. Overall, this study provides strategy for effective therapy.

Язык: Английский

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Targeting cuproptosis for cancer therapy: mechanistic insights and clinical perspectives

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Авг. 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.

Язык: Английский

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Osteocyte mitochondria inhibit tumor development via STING-dependent antitumor immunity

Science Advances, Год журнала: 2024, Номер 10(3)

Опубликована: Янв. 17, 2024

Bone is one of the most common sites tumor metastases. During last step bone metastasis, cancer cells colonize and disrupt matrix, which maintained mainly by osteocytes, abundant in microenvironment. However, role osteocytes metastasis still unclear. Here, we demonstrated that transfer mitochondria to metastatic trigger cGAS/STING-mediated antitumor response. Blocking specifically knocking out mitochondrial Rho GTPase 1 ( Rhot1 ) or mitofusin 2 Mfn2 impaired immunogenicity consequently resulted progression toward matrix. These findings reveal protective against transferring potentially offer a valuable therapeutic strategy for preventing metastasis.

Язык: Английский

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Nanoscale Metal–Organic Frameworks‐Mediated Degradation of Mutant p53 Proteins and Activation of cGAS‐STING Pathway for Enhanced Cancer Immunotherapy

Advanced Science, Год журнала: 2024, Номер 11(12)

Опубликована: Янв. 15, 2024

Abstract Activating cGAS‐STING pathway has great potential to achieve effective antitumor immunotherapy. However, mutant p53 (mutp53), a commonly observed genetic alteration in over 50% of human cancer, will impede the therapeutic performance pathway. Herein, multifunctional ZIF‐8@MnO 2 nanoparticles are constructed degrade mutp53 and facilitate The synthesized can release Zn 2+ Mn cancer cells induce oxidative stress cytoplasmic leakage fragmented mitochondrial double‐stranded DNAs (dsDNAs). Importantly, released induces variable degradation multifarious mutants through proteasome ubiquitination, which alleviate inhibitory effects on In addition, further increases sensitivity cGAS dsDNAs as immunostimulatory signals. Both vitro vivo results demonstrate that effectively promotes synergizes with PD‐L1 checkpoint blockades, leading remarkable regression local tumors well distant metastases breast cancer. This study proposes an inorganic metal ion‐based nanoplatform enhance cGAS‐STING‐mediated immunotherapy, especially those expression.

Язык: Английский

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Regulation of cGAS–STING signalling and its diversity of cellular outcomes

Nature reviews. Immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 7, 2025

Язык: Английский

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Inhalable nanovesicles loaded with a STING agonist enhance CAR-T cell activity against solid tumors in the lung

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Янв. 2, 2025

Suppression of chimeric antigen receptor-modified T (CAR-T) cells by the immunosuppressive tumor microenvironment remains a major barrier to their efficacy against solid tumors. To address this, we develop an anti-PD-L1-expressing nanovesicle loaded with STING agonist cGAMP (aPD-L1 NVs@cGAMP) remodel and thereby enhance CAR-T cell activity. Following pulmonary delivery, nanovesicles rapidly accumulate in lung selectively deliver agonists PD-L1-overexpressing via PD-1/PD-L1 interaction. This targeted delivery effectively avoids systemic inflammation poor cellular uptake that plague free agonists. Internalized trigger signaling induce interferon responses, which diminish populations such as myeloid-derived suppressor promote infiltration. Importantly, anti-PD-L1 single chain variable fragment on surface blocks PD-L1 upregulation induced prevents exhaustion. In both orthotopic cancer metastasis model, combined therapy aPD-L1 NVs@cGAMP potently inhibits growth recurrence. Therefore, is expected serve effective enhancer improve The hindered Here authors report design characterization inhalable cGAMP, showing enhanced activity models.

Язык: Английский

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Self-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy

Journal of the American Chemical Society, Год журнала: 2025, Номер unknown

Опубликована: Янв. 17, 2025

Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and subsequent release DNA (mtDNA), which is anticipated to activate cGAS-STING pathway, thereby augmenting antitumor immune response. However, challenges lie in effectively triggering cancer cells subsequently enhancing activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators cobalt fluoride (CoF2) nanocatalysts for catalytic metalloimmunotherapy. CoF2 a semiconductor structure enzyme-like activity generated substantial amount reactive oxygen species (ROS) under stimulation by endogenous H2O2 exogenous ultrasound. Importantly, discovered that Co-based nanomaterials themselves induce cells. Therefore, initially acted as inducers, caspase-1/GSDMD-dependent via Co2+ ROS, leading mtDNA release. Subsequently, were further utilized STING agonists specifically capable detecting pathway. These cascade events triggered robust response, modulating immunosuppressive tumor microenvironment into an immune-supportive state, providing favorable support therapy. This innovative strategy not only significantly impeded growth primary but also elicited response augment efficacy checkpoint inhibitors preventing distant progression. Overall, this study proposed self-cascade activating amplifying pathway specificity mediated pyroptosis, representing valuable avenue future

Язык: Английский

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Metal Ion Signaling in Biomedicine

Chemical Reviews, Год журнала: 2025, Номер unknown

Опубликована: Янв. 2, 2025

Complex multicellular organisms are composed of distinct tissues involving specialized cells that can perform specific functions, making such life forms possible. Species defined by their genomes, and differences between individuals within a given species directly result from variations in genetic codes. While alterations give rise to disease-causing acquisitions cell identities, it is now well-established biochemical imbalances also lead cellular dysfunction diseases. Specifically, nongenetic chemical events orchestrate metabolism transcriptional programs govern functional identity. Thus, signaling, which broadly defines the conversion extracellular signals into intracellular changes, contribute acquisition diseased states. Metal ions exhibit unique properties be exploited cell. For instance, metal maintain ionic balance cell, coordinate amino acid residues or nucleobases altering folding function biomolecules, catalyze reactions. metals essential signaling effectors normal physiology disease. Deciphering ion challenging endeavor illuminate pathways targeted for therapeutic intervention. Here, we review key processes where play roles describe how targeting has been instrumental dissecting biochemistry this led development effective strategies.

Язык: Английский

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Dendritic cell maturation in cancer

Nature reviews. Cancer, Год журнала: 2025, Номер unknown

Опубликована: Фев. 7, 2025

Язык: Английский

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Adjuvant physiochemistry and advanced nanotechnology for vaccine development

Chemical Society Reviews, Год журнала: 2023, Номер 52(15), С. 5172 - 5254

Опубликована: Янв. 1, 2023

This review provides an introduction of basic principles adjuvanted human vaccines in clinics and summarizes emerging nanotechnology adjuvants vaccine development against cancer infectious diseases.

Язык: Английский

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