Strategic driving of the cancer-immunity cycle in HCC: roles of immune, molecular-targeted, and locoregional therapies.

Abstract

Hepatocellular carcinoma (HCC) treatment has entered the immunotherapy era, characterized by multiple systemic and locoregional therapeutic options. Understanding how each modality modulates the tumor immune microenvironment (TIME) is essential to optimize treatment strategies. The cancer-immunity cycle provides a conceptual basis for antitumor immunity, consisting of a priming phase involving antigen release and T-cell activation, and an effector phase characterized by cytotoxic T-cell-mediated tumor elimination. Immune checkpoint inhibitor (ICI)-based combinations play a central role in HCC treatment. Anti-PD-L1 plus anti-VEGF therapy primarily activates the effector phase by reducing regulatory T cells and macrophages and enhancing cytotoxic T-cell infiltration. In contrast, CTLA-4 blockade-based regimens primarily promote the priming phase by activating CD4⁺ T cells and dendritic cells. Molecular-targeted agents also modulate the TIME. VEGF inhibition commonly reduces immunosuppressive cell populations, lenvatinib enhances cytotoxic T-cell activation through fibroblast growth factor inhibition, and cabozantinib promotes dendritic cell-mediated immune activation via AXL inhibition. Locoregional therapies, including transarterial therapies, stereotactic body radiotherapy, and transarterial radioembolization with Yttrium 90, induce tumor injury, release tumor-associated antigens, and activate inflammatory signaling. In this review, we propose the concept of "strategic driving of the cancer-immunity cycle," in which treatment selection and sequencing are guided by their ability to activate distinct phases of the cycle. This concept may provide a rational strategy to maximize antitumor efficacy in HCC.