Disrupting Tumor Lactate Homeostasis to Sensitize Chemo-Immunotherapy Using a Glucose-Disguised Lactate Interceptor

作者：Xu‐Wen Li, Shuo Geng, Qinjun Chen, Boyu Su, Haolin Song, Jingyi Zhou, Ru Jia, Hongrui Fan, Chufeng Li, Yu Wang, Zonghua Tian, Tao Sun, Chen Jiang · 发表于：ACS Nano · 年份：2025 · DOI：10.1021/acsnano.5c03545 · 被引用次数：6 · 研究领域：Cancer, Hypoxia, and Metabolism、Nanoplatforms for cancer theranostics、Immune cells in cancer

Aberrantly elevated lactate flux in tumors is increasingly recognized as a key driver of metabolic symbiosis, immunosuppression, and, ultimately, immunogenic chemotherapy resistance. Here, we propose a precise lactate homeostasis modulation strategy that selectively intercepts intracellular lactate molecules in highly glycolytic tumor cells. Targeting monocarboxylate transporter 4 (MCT4), a key lactate efflux transporter overexpressed in tumor cells, we developed a glucose-disguised delivery system for precise transport of regulatory molecules into glycolysis-dependent tumor cells. By modulating lactate-mediated crosstalk between heterogeneous tumor subpopulations (glycolysis-dependent and lactate-consuming cells) and immune cells, this strategy effectively disrupts lactate-driven metabolic cooperation within the tumor niche, which may contribute to overcoming lactate-associated resistance to chemo-immunotherapy.