Metabolic Radiosensitization by Targeting Lactate Metabolism with Microfluidic Liposomal Nanocarriers.

Lactate, the main product of the Warburg effect, exerts both intrinsic effects on cancer cell metabolism and noncell autonomous effects that promote tumor development, metastasis, and treatment resistance. As such, glycolytic dependence in tumors is frequently associated with poor clinical outcomes. Targeting lactate metabolism has emerged as a promising strategy to enhance the efficacy of conventional therapies. Here, we investigate the therapeutic potential of targeting lactate metabolism via inhibiting MCT1, MCT4, and MPC in PC3 and FaDu tumor cell models. We confirmed lactate as a substrate that fuels mitochondrial respiration and supports cell survival under hypoxic conditions. Inhibition of lactate influx mediated by 7ACC2 reduced oxygen consumption, sensitizing tumor cells to radiation in both 2D-cell cultures and 3D-spheroid models. Encapsulation of 7ACC2 in DPPC liposomes using microfluidics preserved radiosensitizing activity in both systems, promoting reoxygenation, while overcoming the pharmacological limitations of the free drug. This liposomal formulation therefore represents a promising therapeutic approach to help mitigate hypoxia-induced radioresistance.