Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.

Authors

Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, Ye Chen, Wenhui Wang, Yue Chen, Qiu Sun, Lei Liang, Le Yang, Gaofei Wei

Published in

Nature communications. Jul 04, 2026. Epub Jul 04, 2026.

Abstract

Colorectal cancer (CRC) often exhibits a suppressive tumor microenvironment that is associated with elevated glutamine metabolism and induction of immunosuppressive macrophages. Glutamine antagonists such as 6-diazo-5-oxo-L-norleucine (DON) and its prodrug JHU-083 can limit tumor growth, but their toxicity and immune cell selectivity remain suboptimal. Here, we conjugate DON with the macrophage-targeting moiety artesunate to develop WGF-T17 (T17), which blocks glutamine metabolism in macrophages. In vitro, T17 rewires macrophage metabolism toward glycolysis, inducing lactate buildup and histone lactylation, enhancing mitochondrial fission and phagocytic activity, and thereby reprogramming macrophages to an inflammatory state. In vivo, T17 controls tumor growth better than JHU-083 via macrophage-dependent pathways, and also increases the efficacy of immunotherapy, chemotherapy and anti-angiogenic therapy in female mice carrying subcutaneous CRC tumors. Our findings thus hint T17 as a promising treatment strategy for CRC by targeting macrophage glutamine metabolism to reverse immune suppression.

PMID:
42401559
Bibliographic data and abstract were imported from PubMed on 05 Jul 2026.

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