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Advanced Science

Advanced Science

IF: 14.3
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Tumor Microenvironment‐Responsive Nanoparticles Enhance IDO1 Blockade Immunotherapy by Remodeling Metabolic Immunosuppression

Published:11 December 2024 DOI: 10.1002/advs.202405845 PMID: 39661740
Mengna Wang,?Yuhong Liu,?Yanshi Li,?Tao Lu,?Min Wang,?Zhaobo Cheng,?Lin Chen,?Tongling Wen,?Min Pan,?Guohua Hu

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.

Substances (2)

Materials
Procduct Name CAS Molecular Formula Supplier Price
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 25952-53-8 C8H18ClN3 944 suppliers $9.00-$15216.00
Tetraethyl orthosilicate 78-10-4 C8H20O4Si 474 suppliers $12.00-$1350.00

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