New insights into mechanisms and interventions of locoregional therapies for hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is responsible for a significant number of cancer-related deaths worldwide and its incidence is increasing. Locoregional treatments, which are precision procedures guided by imaging to specifically target liver tumors, play a critical role in the management of a substantial portion of HCC cases. These therapies have become an essential element of the HCC treatment landscape, with transarterial chemoembolization (TACE) being the treatment of choice for patients with intermediate to advanced stages of the disease. Other locoregional therapies, like radiofrequency ablation, are highly effective for small, early-stage HCC. Nevertheless, the advent of targeted immunotherapy has challenged these established treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have shown remarkable efficacy in clinical settings. However, their specific uses and the development of resistance in subsequent treatments have led clinicians to reevaluate the future direction of HCC therapy. This review concentrates on the distinct features of both systemic and novel locoregional therapies. We investigate their effects on the tumor microenvironment at the molecular level and discuss how targeted immunotherapy can be effectively integrated with locoregional therapies. We also examine research findings from retrospective studies and randomized controlled trials on various combined treatment regimens, assessing their validity to determine the future evolution of locoregional therapies within the framework of personalized, comprehensive treatment.

Keywords: Locoregional therapies; hepatocellular carcinoma; immunotherapy; transarterial chemoembolization; tumor microenvironment.

Figure 1

Effect of TACE on the TME: After TACE, HCC locally forms a hypoxic and inflammatory environment, causing HIF-1α to increase. Subsequently, elevated VEGF, b-FGF, angiopoientin-2 stimulate the vascular endothelial cells around the tumor tissue, leading to angiogenesis. Antigens and various pro-inflammatory factors change the immune microenvironment, PD-1+ CD8+ T cells, Tregs decrease, TANs, MDSCs, DCs and TAMs increase. TACE, transcatheter arterial chemoembolization; TME, tumor microenvironment; HCC, hepatocellular carcinoma; HIF-1α, hypoxia inducible factor-1α; VEGF, vascular endothelial growth factor; b-FGF, basic fibroblast growth factor; PD-1, programmed death-1; TAN, tumor associated neutrophils; TAM, tumor associated macrophage; Treg, regulatory T cell; MDSC, myeloid-derived suppressor cell; DC, dendritic cell.

Figure 2

Effect of ablation on the TME: In the early stage after ablation, the local antigens of the tumor stimulate T cell proliferation, and some cytokines recruit NK cells, releasing IFN-γ and TNF-α. Radiofrequency ablation and microwave ablation also form a hypoxic environment after the operation, and the elevated HIF-1α and VEGF promote angiogenesis and EMT, and proinflammatory factors increase some immune suppressive cells such as TAMs, Tregs, MDSCs. While cryoablation will form ice crystals in the cells, promote cell apoptosis and release damage associated molecular patterns, DAMPs, recruit DCs and NK cells. And local freezing will cause vasoconstriction, resulting in local microthrombosis and local hypoxia. TME, tumor microenvironment; NK, natural killer; IFN-γ, Interferon-γ; TNF-α, tumor necrosis factor-α; HIF-1α, hypoxia inducible factor-1α; VEGF, vascular endothelial growth factor; TAM, tumor associated macrophages; Treg, regulatory T cell; MDSC, myeloid derived suppressor cell; DAMP, damage-associated molecular pattern; DC, dendritic cell; MHC, major histocompatibility complex; EMT, epithelial-mesenchymal transition.