Hepatocellular carcinoma: new therapies on the horizon

INTRODUCTION: Although immune checkpoint inhibitor (ICI)-based combinations have established the frontline standard for advanced hepatocellular carcinoma (HCC), substantial unmet needs persist-limited response rates, primary and acquired resistance, absent validated predictive biomarkers, and uncertainty regarding optimal sequencing. Hepatic decompensation may rival tumor progression as a determinant of survival in selected patients. AREAS COVERED: Informed by a focused PubMed and Embase search prioritizing literature (January 2020-April 2026), this review examines near-horizon HCC therapies across three domains: emerging systemic agents beyond first-generation kinase inhibitors, including biomarker-directed strategies; evolving immunotherapy, including neoadjuvant ICI regimens associated with major pathological responses in 20-42%, transarterial chemoembolization-ICI combinations with positive progression-free survival in EMERALD-1 (15.0 vs 8.2 months) and LEAP-012 (14.6 vs 10.0 months), and conversion strategies; and locoregional innovations including personalized yttrium-90 dosimetry, stereotactic body radiation therapy, and histotripsy, a first-in-class FDA-approved noninvasive mechanical ablation modality. Translational considerations including hepatic reserve are also addressed. EXPERT OPINION: Treatment sequencing represents the central operational challenge. Biomarker-informed selection, including emerging humoral immunity signatures, may refine frontline decision-making, although prospective validation is essential. A 'liver-first' management philosophy that prioritizes hepatic reserve alongside tumor control is likely to become integral to clinical practice and trial design.