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      Metallo-alginate hydrogel can potentiate microwave tumor ablation for synergistic cancer treatment

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          Abstract

          Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca 2+ fixed by alginate as Ca 2+-surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca 2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca 2+ homeostasis. Resultantly, Ca 2+-surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn 2+, an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ–formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.

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          Abstract

          A metallo-alginate hydrogel is designed to potentiate MWA treatment by working as MW-susceptible and immunostimulatory agents.

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          Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy

          A therapeutic strategy that can eliminate primary tumours, inhibit metastases, and prevent tumour relapses is developed herein by combining adjuvant nanoparticle-based photothermal therapy with checkpoint-blockade immunotherapy. Indocyanine green (ICG), a photothermal agent, and imiquimod (R837), a Toll-like-receptor-7 agonist, are co-encapsulated by poly(lactic-co-glycolic) acid (PLGA). The formed PLGA-ICG-R837 nanoparticles composed purely by three clinically approved components can be used for near-infrared laser-triggered photothermal ablation of primary tumours, generating tumour-associated antigens, which in the presence of R837-containing nanoparticles as the adjuvant can show vaccine-like functions. In combination with the checkpoint-blockade using anti-cytotoxic T-lymphocyte antigen-4 (CTLA4), the generated immunological responses will be able to attack remaining tumour cells in mice, useful in metastasis inhibition, and may potentially be applicable for various types of tumour models. Furthermore, such strategy offers a strong immunological memory effect, which can provide protection against tumour rechallenging post elimination of their initial tumours.
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            DNA-induced liquid phase condensation of cGAS activates innate immune signaling

            The binding of DNA to cyclic GMP-AMP synthase (cGAS) leads to the production of the secondary messenger cyclic GMP-AMP (cGAMP), which activates innate immune responses. Here, we show that DNA binding to cGAS robustly induced the formation of liquid-like droplets in which cGAS was activated. The disordered and positively charged cGAS N-terminus enhanced cGAS–DNA phase separation by increasing the valencies of DNA binding. Long DNA was more efficient in promoting cGAS liquid phase separation and cGAS enzyme activity than short DNA. Moreover, free zinc ion enhanced cGAS enzyme activity both in vitro and in cells by promoting cGAS–DNA phase separation. These results demonstrated that the DNA-induced phase transition of cGAS promotes cGAMP production and innate immune signaling.
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              Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production.

              Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-β. In vivo, this precipitates an elevation in IFN-β levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent. Copyright © 2014 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: Investigation
                Role: Formal analysisRole: Investigation
                Role: Investigation
                Role: InvestigationRole: Methodology
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: InvestigationRole: MethodologyRole: Resources
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Journal
                Sci Adv
                Sci Adv
                sciadv
                advances
                Science Advances
                American Association for the Advancement of Science
                2375-2548
                August 2022
                03 August 2022
                : 8
                : 31
                : eabo5285
                Affiliations
                [1]Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, 199 Ren’ai Road, Suzhou, 215123 Jiangsu, PR China.
                Author notes
                [* ]Corresponding author. Email: zliu@ 123456suda.edu.cn (Z.L.); lzfeng@ 123456suda.edu.cn (L.F.)
                Author information
                https://orcid.org/0000-0001-5332-5827
                https://orcid.org/0000-0002-9343-6561
                https://orcid.org/0000-0002-2712-050X
                https://orcid.org/0000-0002-1629-1039
                Article
                abo5285
                10.1126/sciadv.abo5285
                9348787
                35921425
                780d1262-8896-4a07-aa33-a0951de49272
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 10 February 2022
                : 16 June 2022
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 22077093
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 52032008
                Funded by: FundRef http://dx.doi.org/10.13039/501100002338, Ministry of Education of the People’s Republic of China;
                Funded by: FundRef http://dx.doi.org/10.13039/501100008804, Ministry of Science and Technology, Government of the People’s Republic of Bangladesh;
                Award ID: 2021YFF0701800
                Funded by: FundRef http://dx.doi.org/10.13039/501100020930, Ministry of Education, Kenya;
                Funded by: Jiangsu Social Development Project;
                Award ID: BE2019658
                Categories
                Research Article
                Biomedicine and Life Sciences
                SciAdv r-articles
                Materials Science
                Life Sciences
                Materials Science
                Custom metadata
                Karla Peñamante

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