通过谷氨酰胺拮抗作用重新编程巨噬细胞免疫代谢增强小鼠的结直肠癌癌症治疗
Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.
摘要(中文译文)
结直肠癌（CRC）常表现出抑制性肿瘤微环境，该微环境与谷氨酰胺代谢升高及免疫抑制性巨噬细胞的诱导相关。谷氨酰胺拮抗剂如6-重氮-5-氧代-L-正亮氨酸（DON）及其前药JHU-083可限制肿瘤生长，但其毒性和免疫细胞选择性仍不理想。在此，我们将DON与巨噬细胞靶向部分青蒿琥酯偶联，开发出WGF-T17（T17），其可阻断巨噬细胞中的谷氨酰胺代谢。在体外，T17将巨噬细胞代谢重编程为糖酵解，诱导乳酸堆积和组蛋白乳酸化，增强线粒体分裂和吞噬活性，从而将巨噬细胞重编程为炎症状态。在体内，T17通过巨噬细胞依赖性途径比JHU-083更好地控制肿瘤生长，并且在携带皮下结直肠癌肿瘤的雌性小鼠中还提高了免疫治疗、化疗和抗血管生成治疗的疗效。因此，我们的研究提示T17通过靶向巨噬细胞谷氨酰胺代谢以逆转免疫抑制，可能成为结直肠癌的一种有前景的治疗策略。
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.
如何引用
AMA
Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, et al. Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.. Nature communications. 2026; doi:10.1038/s41467-026-75208-0.
APA
Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, et al (2026). Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.. Nature communications. https://doi.org/10.1038/s41467-026-75208-0
GB/T 7714
Renming Fan, Xintong Lu, Bingjie Zhang, Zhuang Hou, Ting Zhao, Yongrui Hai, et al. Reprogramming macrophage immunometabolism via glutamine antagonism potentiates colorectal cancer therapy in mice.[J]. Nature communications, 2026 doi:10.1038/s41467-026-75208-0.
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