Transarterial chemoembolisation-based combination therapy as a potential new standard for intermediate-stage hepatocellular carcinoma in the targeted immunotherapy era

Transarterial chemoembolisation (TACE) is the standard therapy for intermediate-stage hepatocellular carcinoma (HCC); however, its efficacy is limited by significant tumour heterogeneity. Recent landmark trials (EMERALD-1 and LEAP-012) demonstrated that adding targeted immunotherapy to TACE significantly improves progression-free survival compared with TACE alone. However, the inconsistent overall survival (OS) benefit, particularly in LEAP-012, highlights the necessity for precision patient stratification. Key determinants of outcomes include tumour burden, liver function, microvascular invasion (MVI), systemic inflammation, immune status and comorbidities. For patients with low tumour burden, optimised locoregional therapies can achieve higher complete response rates. For high tumour burden, multimodal strategies are required, with increasing evidence supporting TACE plus targeted therapy with or without immunotherapy. MVI-positive HCC derives added benefit from adjuvant tyrosine kinase inhibitors (TKIs) after TACE, while dynamic liver function monitoring is crucial for safety, especially in patients with Child-Pugh B. Future directions should focus on developing and validating robust multidimensional stratification models. These models should integrate key established determinants-such as tumour burden, liver function reserve, MVI, systemic inflammatory/immune status, alpha-fetoprotein (AFP) and comorbidities-with promising emerging biomarkers (eg, circulating tumour DNA). Concurrent efforts are needed to optimise combination regimens and conduct health-economic evaluations. Global collaboration and cost-effectiveness analyses are essential to prioritise high-benefit subgroups (eg, those with high tumour burden, MVI positivity and/or mild inflammation, active immune status alongside preserved liver function and limited comorbidities) for intensive combination therapy while avoiding overtreatment in lower-benefit populations.