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

Abstract

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.