ROS responsive nanoparticles mediated inhibition of monocarboxylic acid transporters to enhance chemoimmunotherapy by overcoming low immune response in osteosarcoma

Maintaining intracellular pH homeostasis and regulating the acidity of the tumor microenvironment (TME) are critical for the proliferation and progression of highly glycolytic-dependent cancer cells. This is primarily achieved through the activity of monocarboxylate transporters 1 (MCT1) and monocarboxylate transporters 4 (MCT4), which promotes metabolic symbiosis among tumor cells and enables immune evasion. Consequently, targeting monocarboxylic acid transporters (MCTs) offers an effective strategy for cancer treatment. However, the widespread expression of MCTs and the potential toxicity of MCT inhibitors on normal cells have hindered their clinical utility. Herein, we designed reactive oxygen species (ROS)-sensitive nanoparticles loaded with the MCT1/4 inhibitor syrosingopine (Syro) and cisplatin (IV) prodrugs for the treatment of osteosarcoma. The nanoparticles could efficiently accumulate in the tumor cells and achieve abundant production of ROS, therefore enhancing therapeutic efficacy with the delivery of cisplatin and Syro. The excessive ROS levels induced severe endoplasmic reticulum (ER) stress, triggered immunogenic cell death (ICD), and activated adaptive immunity. This study demonstrates a safe and effective nano-delivery system that enhances tumor chemoimmunotherapy by reshaping lactate distribution in TME, thereby providing an effective new treatment strategy for osteosarcoma.