How Biology Guides the Combination of Locoregional Interventional Therapies and Immunotherapy for Hepatocellular Carcinoma: Cytokines and Their Roles

SIMPLE SUMMARY: Unresectable hepatocellular carcinoma (HCC) is the main type of primary liver cancer and poses a challenge to the healthcare system across the world. Immune checkpoint inhibitor (ICI)-based immunotherapy has become a recent focus of HCC treatment. However, its high risk of treatment-related severe adverse events makes effective combination strategies to lower toxicity and improve clinical outcomes an urgent need. Although locoregional interventional therapies are considered promising strategies to synergize ICI-based immunotherapies by promoting the release of tumor antigens and proinflammatory cytokines, current clinical trials show controversial results. Since cytokines play critical roles in the combination therapy of LITs and immunotherapy, this review aims to summarize the biological roles of cytokines and their therapeutic potentials in the LITs combined with ICI-based immunotherapies. ABSTRACT: As most patients with hepatocellular carcinoma (HCC) are diagnosed at the intermediate or advanced stage and are no longer eligible for curative treatment, the overall survival rate of HCC remains unsatisfactory. Locoregional interventional therapies (LITs), and immune checkpoint inhibitor (ICI)-based immunotherapy, focus on treating HCC, but the efficacy of their individual application is limited. Therefore, the purpose of this review was to discuss the biological roles of cytokines and their therapeutic potential in the combination therapy of LITs and ICI-based immunotherapy. The two common techniques of LITs are ablative and transarterial therapies. Whether LITs are complete or incomplete can largely affect the antitumor immune response and tumor progression. Cytokines that induce both local and systemic responses to LITs, including interferons, interleukins, chemokines, TNF-α, TGF-β, VEGF, and HGF, and their roles are discussed in detail. In addition, specific cytokines that can be used as therapeutic targets to reduce immune-related adverse events (irAEs) are introduced. Overall, incomplete LITs in a tumor, combined with specific cytokines, are thought to be effective at improving the therapeutic efficacy and reducing treatment-induced irAEs, and represent a new hope for managing unresectable HCC.