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Advanced Science

Advanced Science

IF: 14.3
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Immunometabolic Rewiring of Dendritic Cells to Overcome Glutamine-Driven Immune Suppression in Colorectal Cancer

Published:31 October 2025 DOI: 10.1002/advs.202513986 PMID: 41173791
Bingjie Zhang,?Renming Fan,?Yongrui Hai,?Ye Chen,?Xintong Lu,?Wenhui Wang,?Jiarui Dou,?Jiaxin Yan,?Chang Su,?Yue Chen,?Le Yang,?Minggao Zhao,?Lei Liang,?Gaofei Wei

Abstract

The immunosuppressive tumor microenvironment imposes significant metabolic constraints that impair dendritic cell (DC) maturation and antigen presentation, ultimately undermining antitumor immunity. In colorectal cancer (CRC), elevated glutamine uptake by tumor cells depletes extracellular glutamine, thereby limiting DC functionality and disrupting T cell priming. While glutamine antagonists such as JHU083 inhibit tumor metabolism, they are insufficient to fully restore DC activity. Here, the development of T26, a bifunctional immunometabolic prodrug that links JHU083 with the STING agonist MSA-2 via a cleavable amide bond, is reported, enabling synchronized intratumoral release and dual targeting of glutamine metabolism and innate immune activation. In murine CRC models, T26 restores DC maturation, promotes CD8? T cell activation, and reprograms tumor cell-derived extracellular vesicles to enhance antigen presentation and immune stimulation. Importantly, T26 significantly inhibits the growth and proliferation of CRC patient-derived organoids, underscoring its translational potential in human CRC. Notably, T26 also demonstrates strong synergy with chemotherapy, immune checkpoint blockade, and anti-angiogenic therapy, significantly improving tumor control without inducing systemic toxicity. These findings position T26 as a mechanistically integrated and translationally promising strategy to overcome glutamine-driven immune suppression and enhance immunotherapy efficacy in CRC and other metabolically dysregulated malignancies.

Substances (16)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Y-27632 DIHYDROCHLORIDE 146986-50-7 C14H21N3O 277 suppliers $16.00-$2691.10
Y-27632 DIHYDROCHLORIDE 146986-50-7 C14H21N3O 277 suppliers $16.00-$2691.10
Y-27632 DIHYDROCHLORIDE 146986-50-7 C14H21N3O 277 suppliers $16.00-$2691.10
Y-27632 DIHYDROCHLORIDE 146986-50-7 C14H21N3O 277 suppliers $16.00-$2691.10
CALPEPTIN 117591-20-5 C20H30N2O4 142 suppliers $38.00-$1600.00
CALPEPTIN 117591-20-5 C20H30N2O4 142 suppliers $38.00-$1600.00
CALPEPTIN 117591-20-5 C20H30N2O4 142 suppliers $38.00-$1600.00
CALPEPTIN 117591-20-5 C20H30N2O4 142 suppliers $38.00-$1600.00
GW4869 6823-69-4 C30H29ClN6O2 124 suppliers $33.00-$3196.00
GW4869 6823-69-4 C30H29ClN6O2 124 suppliers $33.00-$3196.00

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