HIFU-driven remodeling of fibrotic perivascular myeloid niches in hepatocellular carcinoma: implications for PD-1/PD-L1 blockade

Hepatocellular carcinoma (HCC) usually develops within chronically inflamed and fibrotic liver tissue. This background creates an organ-specific immune niche in which macrophages, sinusoidal endothelial cells, activated stellate cells and extracellular matrix constrain T-cell access and sustain checkpoint-dependent tolerance. Spatial mapping places VEGFA-positive macrophages near CD34-positive endothelium and predicts VEGFA signaling, defining a candidate vascular barrier to PD-1/PD-L1 blockade. High-intensity focused ultrasound (HIFU) can disrupt tumor tissue and may alter this niche. Mechanical HIFU can fragment tumor tissue, release immunogenic material and activate dendritic cells, while focused ultrasound approaches can repolarize macrophages, increase T-cell infiltration and induce adaptive PD-L1 expression. These preclinical effects motivate combination with checkpoint inhibition, while direct niche remodeling in fibrotic HCC remains to be tested. This mini review examines how HIFU may remodel the fibrotic perivascular myeloid niche, why the resulting inflammatory window may sensitize HCC to PD-1/PD-L1 blockade, and which spatial and temporal biomarkers are required for clinical translation.