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Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice
Renming Fan1,2, Xintong Lu1,2, Bingjie Zhang1,2
1Laboratory of Cellular Metabolism and Precision Therapeutics, School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China.
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.
Insights
A novel drug, WGF-T17 (T17), targets glutamine metabolism in immunosuppressive macrophages within colorectal cancer (CRC) tumors. This approach shows promise for enhancing cancer treatments by reprogramming immune cells and controlling tumor growth.
Area of Science:
- Oncology
- Immunology
- Metabolic pathways
Background:
- Colorectal cancer (CRC) is characterized by a suppressive tumor microenvironment.
- Elevated glutamine metabolism and immunosuppressive macrophages contribute to CRC progression.
- Existing glutamine antagonists (DON, JHU-083) have toxicity and selectivity issues.
Purpose of the Study:
- To develop a novel therapeutic agent targeting macrophage glutamine metabolism in CRC.
- To investigate the efficacy of WGF-T17 (T17) in reprogramming macrophages and controlling tumor growth.
- To evaluate T17's potential to enhance existing cancer therapies.
Main Methods:
- Conjugation of 6-diazo-5-oxo-L-norleucine (DON) with artesunate to create T17.
- In vitro analysis of T17's effects on macrophage metabolism, including glycolysis, lactate production, and phagocytosis.
- In vivo studies in female mice with subcutaneous CRC tumors to assess tumor growth control and combination therapy efficacy.
Main Results:
- T17 effectively blocks glutamine metabolism in macrophages, shifting their metabolism towards glycolysis.
- In vitro, T17 induces lactate buildup, histone lactylation, mitochondrial fission, and enhanced phagocytic activity, promoting an inflammatory macrophage phenotype.
- In vivo, T17 demonstrated superior tumor growth control compared to JHU-083 via macrophage-dependent mechanisms and improved outcomes when combined with immunotherapy, chemotherapy, and anti-angiogenic therapy.
Conclusions:
- WGF-T17 (T17) is a promising therapeutic strategy for colorectal cancer.
- Targeting macrophage glutamine metabolism with T17 can reverse immune suppression within the tumor microenvironment.
- T17 holds potential for combination therapies to improve CRC treatment efficacy.
