Spatiotemporal dynamics of the tumor microenvironment in hepatocellular carcinoma during combination immunotherapy

作者：Iwasaki H, Itoh S, Toshida K, Mita J, Ishikawa T, Iseda N, Yugawa K, Yoshiya S, Motomura T, Toshima T, Aishima S, Oda Y, Yoshizumi T · 发表于：Hepatology communications · 年份：2026 · DOI：10.1097/HC9.0000000000001014 · 被引用次数：30 · 研究领域：Liver Neoplasms、Carcinoma, Hepatocellular、Tumor Microenvironment、Bevacizumab、Immunotherapy、Antineoplastic Combined Chemotherapy Protocols、Humans、CD8-Positive T-Lymphocytes、Receptors, Immunologic、Female、Male、Single-Cell Analysis

BACKGROUND: Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood. METHODS: We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry. RESULTS: These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater...