Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression
Abstract The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME‐responsive nanoparticles (HMP...
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Wiley
2025-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405845 |
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| author | Mengna Wang Yuhong Liu Yanshi Li Tao Lu Min Wang Zhaobo Cheng Lin Chen Tongling Wen Min Pan Guohua Hu |
| author_facet | Mengna Wang Yuhong Liu Yanshi Li Tao Lu Min Wang Zhaobo Cheng Lin Chen Tongling Wen Min Pan Guohua Hu |
| author_sort | Mengna Wang |
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| description | Abstract The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME‐responsive nanoparticles (HMP1G NPs) loaded with 1‐methyltryptophan (1‐MT; an indoleamine 2,3‐dioxygenase 1 [IDO1] inhibitor,) and S‐nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1‐MT‐mediated ICB. The HMP1G NPs responded to H+ and glutathione in the TME, releasing Mn2+, GSNO, and 1‐MT. The released Mn2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1‐MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell‐derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano‐platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy. |
| format | Article |
| id | doaj-art-4aaea9b9f07d4ed08809dd43fa03f013 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-4aaea9b9f07d4ed08809dd43fa03f0132025-02-04T13:14:54ZengWileyAdvanced Science2198-38442025-02-01125n/an/a10.1002/advs.202405845Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic ImmunosuppressionMengna Wang0Yuhong Liu1Yanshi Li2Tao Lu3Min Wang4Zhaobo Cheng5Lin Chen6Tongling Wen7Min Pan8Guohua Hu9Department of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaDepartment of Otorhinolaryngology The First Affiliated Hospital of Chongqing Medical University Chongqing 400016 P. R. ChinaAbstract The clinical efficacy of immune checkpoint blockade (ICB) therapy is significantly compromised in the metabolically disordered tumor microenvironment (TME), posing a formidable challenge that cannot be ignored in current antitumor strategies. In this study, TME‐responsive nanoparticles (HMP1G NPs) loaded with 1‐methyltryptophan (1‐MT; an indoleamine 2,3‐dioxygenase 1 [IDO1] inhibitor,) and S‐nitrosoglutathione (GSNO; a nitric oxide donor) is developed to enhance the therapeutic efficacy of 1‐MT‐mediated ICB. The HMP1G NPs responded to H+ and glutathione in the TME, releasing Mn2+, GSNO, and 1‐MT. The released Mn2+ catalyzed the production of abundant reactive oxygen species and nitric oxide from hydrogen peroxide and GSNO, and the generated nitric oxide, synergistically with 1‐MT, inhibited the accumulation of kynurenine mediated by IDO1 in the tumor. Mechanistically, HMP1G NPs downregulated tumor cell‐derived IDO1 via the aryl hydrocarbon receptor/signal transducer and activator of transcription 3/interleukin signaling axis to improve kynurenine/tryptophan metabolism and immunosuppression. In a murine breast cancer model, treatment with HMP1G NPs elicited effective antitumor immunity and enhanced survival outcomes. This study highlights a novel nano‐platform that simultaneously improves metabolism and enhances ICB efficacy to achieve a new and efficient antitumor strategy.https://doi.org/10.1002/advs.202405845chemodymic therapyimmunosuppressionindoleamine 2,3‐dioxygenase 1KYN/TRP metabolism |
| spellingShingle | Mengna Wang Yuhong Liu Yanshi Li Tao Lu Min Wang Zhaobo Cheng Lin Chen Tongling Wen Min Pan Guohua Hu Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression Advanced Science chemodymic therapy immunosuppression indoleamine 2,3‐dioxygenase 1 KYN/TRP metabolism |
| title | Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression |
| title_full | Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression |
| title_fullStr | Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression |
| title_full_unstemmed | Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression |
| title_short | Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression |
| title_sort | tumor microenvironment responsive nanoparticles enhance ido1 blockade immunotherapy by remodeling metabolic immunosuppression |
| topic | chemodymic therapy immunosuppression indoleamine 2,3‐dioxygenase 1 KYN/TRP metabolism |
| url | https://doi.org/10.1002/advs.202405845 |
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