Portal vein tumor thrombus in hepatocellular carcinoma: an immune sanctuary driving immune exclusion and therapeutic resistance

Abstract

Background: Portal vein tumor thrombus (PVTT) is the most common form of macrovascular invasion in hepatocellular carcinoma (HCC) and is associated with poor prognosis, rapid intrahepatic dissemination, and limited responsiveness to systemic therapy. Increasing evidence indicates that PVTT is not merely an intravascular extension of the primary tumor, but rather a biologically distinct and highly adaptive immunosuppressive niche that contributes to immune escape and therapeutic resistance. Summary: This review summarizes current genomic, transcriptomic, single-cell, and spatially resolved evidence regarding the immune landscape of PVTT in HCC. We discuss how early clonal divergence, hypoxia-associated metabolic rewiring, and stromal-vascular remodeling cooperatively shape the PVTT microenvironment. PVTT is characterized by enrichment of suppressive myeloid populations, activation of cancer-associated fibroblast programs, extracellular matrix accumulation, endothelial barriers to immune-cell trafficking, and progressive dysfunction or exclusion of effector lymphocytes. Together, these features establish a strongly immune-excluded and immunosuppressive ecosystem, providing a mechanistic basis for the limited efficacy of immune checkpoint blockade in patients with HCC-PVTT. We further highlight the translational implications of this framework for biomarker development, patient stratification, and rational combination strategies targeting suppressive myeloid and stromal programs, vascular barriers, and metabolic-immune crosstalk. Key Messages: PVTT should be regarded as a distinct immunosuppressive niche rather than a passive vascular extension of the primary tumor. Its immune landscape is shaped by coordinated interactions among tumor evolution, metabolic adaptation, stromal remodeling, and immune dysfunction. A better mechanistic understanding of PVTT may support biomarker-guided stratification and the development of more effective precision therapies for HCC with macrovascular invasion.