An ultrasound-visualized methionine partitioning nano-modulator for enhanced immunotherapy against anti-PD-1 resistant tumors

Metabolic competition and accumulation of metabolic byproducts in the tumor microenvironment (TME) severely impair the antitumor functions of T cells, leading to suboptimal outcomes in cancer immunotherapy. To address these challenges, we developed an ultrasound-visualized methionine partitioning nano-modulator utilizing erythrocyte membrane-hybridized liposomes loaded with the glycolysis inhibitor lonidamine (LND) and small interfering RNA (siRNA) against methionine transporter solute carrier family 43, member 2 (SLC43A2). By downregulating SLC43A2 expression to reduce methionine uptake by tumor cells and suppressing tumor glycolysis to alleviate the acidic TME, the nano-modulator enhances methionine availability for T cells and improves T cell activity. Moreover, the oxygen-enriched perfluorohexane (PFH-O 2 ) loaded in the core of the nano-modulator alleviates tumor hypoxic, further reducing the glycolysis rate of tumor cells. Furthermore, ultrasound-triggered liquid-gas phase transitions enable real-time ultrasound contrast imaging for precise tumor visualization, while leveraging the ultrasonic cavitation effect to enhance drug penetration and release at the tumor site. In summary, this ultrasound-visualized methionine partitioning nano-modulator effectively reshapes tumor metabolism and immunosuppressive TME under ultrasound guidance, thereby significantly improving the efficacy of tumor immunotherapy. These findings demonstrate a promising strategy for enhancing immunotherapy outcomes through metabolic modulation and microenvironment regulation.