Sonodynamic therapy augmented by glycolysis inhibition: a novel metabolic reprogramming strategy for enhanced osteosarcoma treatment

Abstract A metabolic reprogramming strategy, considered an efficient way to enhance current therapies, has provided renewed hope for treating osteosarcoma (OS), which has reached a bottleneck in clinical practice. In this study, SHK@Mn-TiO2 were developed as novel SDT agents with glycolysis-inhibiting properties. By reducing the expression of PKM2 and HK-2, SHK@Mn-TiO2 effectively inhibited glycolysis, thereby reversing the hypoxic TME, as evidenced by more than ∼ 50% decrease in HIF-1α and lactate (LA) levels compared with those of Mn-TiO2. Under this O2-enriched TME, SHK@Mn-TiO2 enhanced intracellular reactive oxygen species (ROS) levels by approximately 53% and increased K7M2 tumor inhibition under ultrasound (US). Furthermore, the combination of glycolysis inhibition and SDT initiated a cascade of immune responses, promoting a ∼ 98% increase in the maturation of dendritic cells and a ∼ 280% increase in the infiltration of IFN-γ+ CD8+ T cells compared with those in the control. The typically immunosuppressive TME induced by conventional SDT was significantly reversed, as indicated by the reduction in the proportions of regulatory T cells to ∼ 18% and myeloid-derived suppressor cells (MDSCs) to ∼ 49% in the Mn-TiO2 groups. Moreover, a long-term immune memory effect was observed in the K7M2 tumor rechallenge model as a result of strong immune activation. Overall, this study highlights a sono-immune strategy for OS treatment based on the synergistic effects of glycolysis inhibition combined with SDT, offering a promising solution to the current therapeutic challenges in clinical OS management.