Metabolic Reprogramming Nanoplatform for Broad-Spectrum Lactate Suppression to Reverse High Intensity Focused Ultrasound-Induced Immunosuppression in Hepatocellular Carcinoma Therapy.

High intensity focused ultrasound (HIFU) ablation holds significant clinical potential for hepatocellular carcinoma (HCC) treatment but is limited by incomplete ablation and recurrence. Recent studies have revealed that HIFU ablation frequently induces sublethal heat stress and exacerbates hypoxic conditions, thereby triggering metabolic reprogramming in tumor cells. This is characterized by a pronounced Warburg effect, elevated lactate level, and a consequent intensification of the immunosuppressive tumor microenvironment (ITM). In response, we designed and synthesized a multifunctional lactate metabolism regulatory nanoplatform. This formulation employed cyclic Arg-Gly-Asp (cRGD) peptide-modified liposomes as a carrier for tumor-specific targeting. Its core comprised perfluorohexane (PFH), which underwent a phase transition to generate microbubbles upon ultrasound activation, thereby enhancing the local acoustic field and reducing the required HIFU output power. This approach mitigated sublethal heat stress and suppressed heat-induced lactate production in the cells. Simultaneously, PFH encapsulated high-concentration oxygen to increase tumor oxygen partial pressure, inhibit hypoxia inducible factor-1α, and downregulate glucose transporter 1 (GLUT1), thereby diminishing glucose uptake by tumor cells. The shell coloaded BAY-876, a GLUT1 inhibitor, directly suppressed residual GLUT1 activity, further obstructing glucose uptake and synergistically reducing lactate production. Ultimately, this integrated approach achieved a maximum 3.23-fold reduction in lactate levels, significantly alleviating lactate-mediated ITM and effectively suppressing tumor growth in HCC mice following HIFU treatment through broad-spectrum lactate modulation. Collectively, this provides a promising metabolic immunomodulatory strategy for the local treatment of HCC.