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

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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Bibliographic Details
Main Authors: Mengna Wang, Yuhong Liu, Yanshi Li, Tao Lu, Min Wang, Zhaobo Cheng, Lin Chen, Tongling Wen, Min Pan, Guohua Hu
Format: Article
Language:English
Published: Wiley 2025-02-01
Series:Advanced Science
Subjects:
chemodymic therapy
immunosuppression
indoleamine 2,3‐dioxygenase 1
KYN/TRP metabolism
Online Access:https://doi.org/10.1002/advs.202405845
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Summary: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.
ISSN:2198-3844

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