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A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.

Shuai Guo·Xiaoke Wang·Huiwan Chen·Xiaopan Chen·Tianyu Li·Xueqin Shi·Baoyan Ou·Juntao Yuan·Zhilu Yang·Jun Zhou·Shaohui Deng·Yang Liu·Xing-Jie Liang·Caiwen Ou
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Abstract

Breast cancer exhibits a profoundly immunosuppressive tumor microenvironment (TME), where innate immune silence prevents antigen sensing and persistent T cell exhaustion limits effector responses, rendering most immunotherapies ineffective. Clinical profiling of 1093 The Cancer Genome Atlas (TCGA) cases identified a glucose-fueled glutathione (GSH)-glutathione peroxidase 4 (GPX4)-dihydrolipoamide S-acetyltransferase (DLAT) axis as a dominant metabolic shield that suppresses oxidative stress, and thereby enforces both stimulator of interferon genes (STING) silence and CD8+ T cell exclusion. To dismantle this barrier, we developed an immunometabolic nanotherapy, GOx/ES-CO-LDH@TIGIT-Nanotrap (TNT). In acidic tumors, proton-driven layered double hydroxide (LDH) disassembly releases glucose oxidase (GOx) and extremely small cuprous oxide (ES-CO). GOx depletes glucose and nicotinamide adenine dinucleotide phosphate (NADPH) to induce disulfidptosis, while ES-CO releases cuprous ions (Cu+) that trigger cuproptosis via binding to lipoylated mitochondrial proteins. Their mutual biochemical amplification produces a cycloacclerated disulfidptosis-cuproptosis cascade that collapses the GSH-GPX4-DLAT axis and restores STING activation. Meanwhile, the macrophage-derived T cell immunoreceptor with Ig and ITIM domains (TIGIT) Nanotrap sequesters CD155 to prevent T cell suppression. Together, this coordinated innate reactivation and adaptive rescue converts immune-cold tumors into STING-inflamed and T cell responsive lesions.

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FemaleT-Cell ExhaustionHumansAnimalsBreast NeoplasmsImmunity, InnateSTING ProteinMembrane ProteinsReceptors, ImmunologicNanoparticlesTumor MicroenvironmentMiceDisulfidptosisImmunotherapyCell Line, TumorcGAS-STING Signaling PathwayCuproptosisInnate immune silenceSTING-activable immunometabolic nanotherapyT cell exhaustionTIGIT nanotrapJournal ArticleResearch Support, Non-U.S. Gov't

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Shuai Guo, Xiaoke Wang, Huiwan Chen, Xiaopan Chen, Tianyu Li, Xueqin Shi, Baoyan Ou, Juntao Yuan, Zhilu Yang, Jun Zhou, Shaohui Deng, Yang Liu, Xing-Jie Liang, Caiwen Ou. 2026-06-18. A TIGIT nanotrapping-guided STING-activatable immunometabolic strategy overcomes innate immune silence and T cell exhaustion in breast cancer.. https://doi.org/10.1016/j.jconrel.2026.115111

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