Elesclomol Loaded Copper Oxide Nanoplatform Triggers Cuproptosis to Enhance Antitumor Immunotherapy

Advanced Science, Journal Year: 2024, Volume and Issue: 11(18)

Published: March 2, 2024

Abstract The induction of cuproptosis, a recently identified form copper‐dependent immunogenic cell death, is promising approach for antitumor therapy. However, sufficient accumulation intracellular copper ions (Cu 2+ ) in tumor cells essential inducing cuproptosis. Herein, an intelligent cuproptosis‐inducing nanosystem constructed by encapsulating oxide (CuO) nanoparticles with the ionophore elesclomol (ES). After uptake cells, ES@CuO degraded to release Cu and ES synergistically trigger thereby significantly inhibiting growth murine B16 melanoma cells. Moreover, further promoted cuproptosis‐mediated immune responses reprogrammed immunosuppressive microenvironment increasing number tumor‐infiltrating lymphocytes secreted inflammatory cytokines. Additionally, combining programmed death‐1 (PD‐1) immunotherapy substantially increased efficacy melanoma. Overall, findings this study can lead use novel strategy therapy, which may enhance checkpoint inhibitor

Language: Английский

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Ferroptosis in immunostimulation and immunosuppression

Immunological Reviews, Journal Year: 2023, Volume and Issue: 321(1), P. 199 - 210

Published: July 9, 2023

Summary Ferroptosis is a form of iron‐dependent regulated cell death characterized by the accumulation toxic lipid peroxides, particularly in plasma membrane, leading to lytic death. While it plays crucial role maintaining overall health and proper functioning multicellular organisms, can also contribute tissue damage pathological conditions. Although ferroptotic generally recognized as an immunostimulatory process associated with release damage‐associated molecular patterns (DAMPs), occurrence ferroptosis immune cells or immunosuppressive molecules result tolerance. Consequently, there ongoing exploration targeting upstream signals machinery therapeutically enhance inhibit response. In addition introducing core mechanisms ferroptosis, we will focus on characteristics conditions, context infection, sterile inflammation, tumor immunity.

Language: Английский

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The crosstalk of CD8+ T cells and ferroptosis in cancer

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 14

Published: Jan. 15, 2024

Ferroptosis is an iron-dependent, novel form of programmed cell death characterized by lipid peroxidation and glutathione depletion widespread in a variety diseases. CD8+ T cells are the most important effector cytotoxic cells, capable specifically recognizing killing cancer cells. Traditionally, thought to induce mainly through perforin granzyme, Fas-L/Fas binding. In recent years, cell-derived IFN-γ was found promote ferroptosis multiple mechanisms, including upregulation IRF1 IRF8, downregulation system XC-, while shown enhance anti-tumor effects heating tumor immune microenvironment exposure release tumor-associated specific antigens, which results positive feedback pathway. Unfortunately, intra-tumoral more sensitive than limits application inducers cancer. addition, susceptible being regulated other TME, such as macrophages, dendritic Treg, bone marrow-derived immunosuppressive Together, these factors build complex network Therefore, we aim integrate relevant studies reveal potential mechanisms crosstalk between ferroptosis, summarize preclinical models therapy find new therapeutic strategies this review.

Language: Английский

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HMGB1 in the interplay between autophagy and apoptosis in cancer

Cancer Letters, Journal Year: 2023, Volume and Issue: 581, P. 216494 - 216494

Published: Nov. 24, 2023

Language: Английский

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Emerging insights into cuproptosis and copper metabolism: implications for age-related diseases and potential therapeutic strategies

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: April 23, 2024

The expanding geriatric population, whose predisposition toward disabling morbidities and age-related diseases (ARD) is well-documented, has become a paramount social issue, exerting an onerous burden on both the healthcare industry wider society. ARD manifest as progressive deterioration of bodily tissues organs, eventually resulting in failure these vital components. At present, no efficacious measures exist to hinder onset ARD. Copper, essential trace element, involved wide range physiological processes across different cell types. In recent research, novel variant copper-dependent death, termed cuproptosis, been identified. This mode cellular demise stands apart from previously recognized types death. Cuproptosis occurs when copper binds with acyl-CoA synthetase tricarboxylic acid (TCA) cycle, protein aggregation toxicity stress, ultimately leading this paper, we provide concise overview current understanding concerning metabolism copper, copper-related diseases, hallmarks toxicity, mechanisms that regulate toxicity. Additionally, discuss implications cuproptosis mutations development ARD, well potential for targeting treatment

Language: Английский

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Novel Biomarkers for Diagnosis and Monitoring of Immune Thrombocytopenia

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4438 - 4438

Published: Feb. 23, 2023

Lower-than-normal platelet counts are a hallmark of the acquired autoimmune illness known as immune thrombocytopenia, which can affect both adults and children. Immune thrombocytopenia patients' care has evolved significantly in recent years, but disease's diagnosis not, it is still only clinically achievable with elimination other causes thrombocytopenia. The lack valid biomarker or gold-standard diagnostic test, despite ongoing efforts to find one, adds high rate disease misdiagnosis. However, several studies have helped elucidate number features etiology, highlighting how loss not caused by an increase peripheral destruction also involves humoral cellular system effectors. This made possible identify role immune-activating substances such cytokines chemokines, complement, non-coding genetic material, microbiome, gene mutations. Furthermore, megakaryocyte immaturity indices been emphasized new markers, prognostic signs responses particular types therapy suggested. Our review's goal was compile information from literature on novel biomarkers, markers that will help us improve management these patients.

Language: Английский

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Susceptibility of acute myeloid leukemia cells to ferroptosis and evasion strategies

Frontiers in Molecular Biosciences, Journal Year: 2023, Volume and Issue: 10

Published: Sept. 25, 2023

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy with 5-year survival rate of less than 30%. Continuous updating diagnostic and therapeutic strategies has not been effective in improving the clinical benefit AML. AML cells are prone to iron metabolism imbalance due their unique pathological characteristics, ferroptosis novel cell death mode that dominated by three cellular biological processes: metabolism, oxidative stress lipid metabolism. An in-depth exploration mechanism can provide new insights for diagnosis treatment this disease. This study summarizes recent studies on suggests metabolic gene mutation patterns, dependence mitochondria greatly increase susceptibility ferroptosis. In addition, establish variety evade maintain during process occurrence development, related drugs targeting pathway treatment, which provides development directions subsequent research

Language: Английский

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Advancements in Stimulus-Responsive Co-Delivery Nanocarriers for Enhanced Cancer Immunotherapy

International Journal of Nanomedicine, Journal Year: 2024, Volume and Issue: Volume 19, P. 3387 - 3404

Published: April 1, 2024

Abstract: Cancer immunotherapy has emerged as a novel therapeutic approach against tumors, with immune checkpoint inhibitors (ICIs) making significant clinical practice. The traditional ICIs, PD-1 and PD-L1, augment the cytotoxic function of T cells through inhibition tumor evasion pathways, ultimately leading to initiation an antitumor response. However, implementation ICIs encounters obstacles stemming from existence immunosuppressive microenvironment inadequate infiltration CD8 + cells. Considerable attention been directed towards advancing immunogenic cell death (ICD) potential solution counteract microenvironment. This holds promise in transforming "cold" tumors into "hot" that exhibit responsiveness antitumor. By combining ICD synergistic response can be achieved. combination inducers PD-1/PD-L1 is hindered by issues such poor targeting uncontrolled drug release. An advantageous presented stimulus-responsive nanocarrier integrating physicochemical properties inhibitors, facilitating precise delivery specific tissues for optimal therapy. Moreover, these nanocarriers leverage distinct features accomplish controlled release regulate kinetics delivery. article aims investigate advancement co-delivery utilizing inhibitors. Special focus dedicated exploring advantages recent advancements this system enabling inducers. molecular mechanisms are concisely summarized. In conclusion, we examine research prospects challenges could greatly enhance immunotherapeutic approaches cancer treatment. Keywords: therapy, death, co-delivery, immune-checkpoint

Language: Английский

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Targeting BMAL1 reverses drug resistance of acute myeloid leukemia cells and promotes ferroptosis through HMGB1-GPX4 signaling pathway

Journal of Cancer Research and Clinical Oncology, Journal Year: 2024, Volume and Issue: 150(5)

Published: May 4, 2024

Abstract Purpose Acute myeloid leukemia (AML) is a refractory hematologic malignancy that poses serious threat to human health. Exploring alternative therapeutic strategies capable of inducing modes cell death, such as ferroptosis, holds great promise viable and effective intervention. Methods We analyzed online database data collected clinical samples verify the expression function BMAL1 in AML. conducted experiments on AML proliferation, cycle, chemotherapy resistance by overexpressing/knocking down using assays MDA detection BODIPY 581/591 C11 staining. validated transcriptional regulation HMGB1 through ChIP assay, luciferase RNA level detection, western blotting. Finally, we confirmed results our at animal level. Results up-regulation an observed phenomenon patients. Furthermore, there existed strong correlation between elevated levels inferior prognosis individuals with found knocking inhibited growth blocking cycle. Conversely, overexpressing promoted proliferation. Moreover, research revealed ferroptosis cells BMAL1-HMGB1-GPX4 pathway. can enhance efficacy certain first-line cancer drugs, including venetoclax, dasatinib, sorafenib. Conclusion Our suggest plays crucial regulatory role drug resistance, ferroptosis. could be potential important target for

Language: Английский

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NFE2L2 and SLC25A39 drive cuproptosis resistance through GSH metabolism

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Nov. 28, 2024

Cuproptosis is a recently discovered form of regulated cell death triggered by mitochondrial copper accumulation and proteotoxic stress. Here, we provide the first evidence that glutathione (GSH), major non-protein thiol in cells, acts as cuproptosis inhibitor pancreatic ductal adenocarcinoma (PDAC) cells. Mechanistically, GSH inhibits chelating copper, contrasting its role blocking ferroptosis inhibiting lipid peroxidation. The classical inducer, ES-Cu (elesclomol plus copper), increases protein stability transcription factor NFE2L2 (also known NRF2), leading to upregulation gene expression glutamate-cysteine ligase modifier subunit (GCLM) catalytic (GCLC). GCLM GCLC are rate-limiting enzymes synthesis, increased transported into mitochondria via solute carrier family 25 member 39 (SLC25A39) transporter. Consequently, genetic inhibition NFE2L2-GSH-SLC25A39 pathway enhances cuproptosis-mediated tumor suppression culture mouse models. These findings not only reveal distinct mechanisms ferroptosis, but also suggest potential combination strategy suppress PDAC growth.

Language: Английский

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