Tumor microenvironment governs various therapeutic tolerability of cancer such as ferroptosis and immuno-therapy through rewiring tumor metabolic reprogramming like Warburg metabolism.Highly expressed carbonic anhydra...Tumor microenvironment governs various therapeutic tolerability of cancer such as ferroptosis and immuno-therapy through rewiring tumor metabolic reprogramming like Warburg metabolism.Highly expressed carbonic anhydrases(CA)in tumor that maintaining the delicate metabolic homeostasis is thus the most potential target to be modulated to resolve the therapeutic tolerability.Hence,in this article,a self-healable and pH-responsive spermidine/ferrous ion hydrogel loaded with CA inhibitor(acetazolamide,ACZ)and glucose oxidase(ACZ/GOx@SPM-HA Gel)was fabricated through the Schiff-base reaction between spermidine-dextran and oxidized hyaluronic acid,along with ferrous coordination.Investigation on cancer cell lines(MOC-1)demonstrated ACZ/GOx@SPM-HA Gel may induce cellular oxidative stress and mitochondrial dysfunction through disrupting the cellular homeostasis.Moreover,with the facilitation of autophagy induced by spermidine,ACZ/GOx@SPM-HA Gel may trigger a positive feedback loop to maximally amplify cellular ferroptosis and promote DAMPs release.The anti-tumor evaluation on xenograft mice models furtherly proved the local injection of such hydrogel formulation could efficiently inhibit the tumor growth and distinctively promote the immunogenicity of tumor bed to provide a more favorable environment for immunotherapy.Overall,ACZ/GOx@SPM-HA Gel,with such feasible physiochemical properties and great biocompatibility,holds great potential in treating solid tumors with acidosis-mediated immunotherapy tolerance.展开更多
The tricarboxylic acid(TCA)cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions.Although tumor metabolic reprogramming places aerobic glycolysis in a dominant posit...The tricarboxylic acid(TCA)cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions.Although tumor metabolic reprogramming places aerobic glycolysis in a dominant position,the TCA cycle remains indispensable for tumor cells as a hub for the metabolic linkage and interconversion of glucose,lipids,and certain amino acids.TCA intermediates such as citrate,α-ketoglutarate,succinate,and fumarate are altered in tumors,and they regulate the tumor metabolism,signal transduction,and immune environment to affect tumorigenesis and tumor progression.This article provides a comprehensive review of the modifications occurring in tumor cells in relation to the intermediates of the TCA cycle,which affects tumor pathogenesis and current therapeutic strategy for therapy through targeting TCA cycle in cancer cells.展开更多
基金supported by the Science and Technology Program of Guangzhou(2024A03J0431 and 2023A03J0488)National Natural Science Foundation of China(52173150 and U22A20315)+1 种基金the Guangzhou Science and Technology Program City-University Joint Funding Project(2024A03J0604)Guangdong Basic and Applied Basic Research Foundation(2023A1515111126).
文摘Tumor microenvironment governs various therapeutic tolerability of cancer such as ferroptosis and immuno-therapy through rewiring tumor metabolic reprogramming like Warburg metabolism.Highly expressed carbonic anhydrases(CA)in tumor that maintaining the delicate metabolic homeostasis is thus the most potential target to be modulated to resolve the therapeutic tolerability.Hence,in this article,a self-healable and pH-responsive spermidine/ferrous ion hydrogel loaded with CA inhibitor(acetazolamide,ACZ)and glucose oxidase(ACZ/GOx@SPM-HA Gel)was fabricated through the Schiff-base reaction between spermidine-dextran and oxidized hyaluronic acid,along with ferrous coordination.Investigation on cancer cell lines(MOC-1)demonstrated ACZ/GOx@SPM-HA Gel may induce cellular oxidative stress and mitochondrial dysfunction through disrupting the cellular homeostasis.Moreover,with the facilitation of autophagy induced by spermidine,ACZ/GOx@SPM-HA Gel may trigger a positive feedback loop to maximally amplify cellular ferroptosis and promote DAMPs release.The anti-tumor evaluation on xenograft mice models furtherly proved the local injection of such hydrogel formulation could efficiently inhibit the tumor growth and distinctively promote the immunogenicity of tumor bed to provide a more favorable environment for immunotherapy.Overall,ACZ/GOx@SPM-HA Gel,with such feasible physiochemical properties and great biocompatibility,holds great potential in treating solid tumors with acidosis-mediated immunotherapy tolerance.
基金supported by grant nos.82073458,82173424,81974476,and 82221002 from the National Natural Science Foundationby grant from The Scientific Research Program of FuRong Laboratory(no.2023SK2103)+1 种基金by the Science and Technology Innovation Program of Hunan Province(2021RC4013)as well as the key project in Hunan province(2024JJ3052).
文摘The tricarboxylic acid(TCA)cycle is capable of providing sufficient energy for the physiological activities under aerobic conditions.Although tumor metabolic reprogramming places aerobic glycolysis in a dominant position,the TCA cycle remains indispensable for tumor cells as a hub for the metabolic linkage and interconversion of glucose,lipids,and certain amino acids.TCA intermediates such as citrate,α-ketoglutarate,succinate,and fumarate are altered in tumors,and they regulate the tumor metabolism,signal transduction,and immune environment to affect tumorigenesis and tumor progression.This article provides a comprehensive review of the modifications occurring in tumor cells in relation to the intermediates of the TCA cycle,which affects tumor pathogenesis and current therapeutic strategy for therapy through targeting TCA cycle in cancer cells.
