Combining liver-directed and immunotherapy in advanced hepatocellular carcinoma: A review and future directions

Hepatocellular carcinoma (HCC) is a highly morbid tumor with diverse genomic heterogeneity that poses a major therapeutic barrier. Systemic immunotherapy is often considered in the treatment of advanced HCC, but immunotherapy has been limited by high rates of resistance and immune evasion. Newer studies have explored the combination of locoregional treatments (LRTs), a common approach to intermediate-stage HCC or as a bridge to transplant, with immunotherapy. This review explores the current evidence regarding combination systemic immunotherapy with locoregional transarterial, ablation, and histotripsy modalities, as well as leading theories on the mechanism of their synergistic effects. Combinations of transarterial or ablative therapy with multikinase (MKIs) or immune checkpoint inhibitors (ICIs) have been linked to prolonged survival and delayed tumor progression/recurrence, though treatment-induced adverse effects remain an important consideration. Ablation and histotripsy may augment the efficacy of immunotherapy through the abscopal effect, in which subsequent immune response to local tumor destruction may enhance immunogenic cell death, even in satellite, untreated lesions. Newer management strategies may utilize circulating tumor DNA (ctDNA) for improved surveillance and early detection of recurrence.