Integrating Combination Therapy and Smart Embolic Materials to Overcome the Therapeutic Ceiling of Transarterial Chemoembolization in Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) remains standard for intermediate-stage hepatocellular carcinoma (HCC), but its long-term efficacy is limited by post-embolic hypoxia-driven angiogenesis and high recurrence rates. Combining TACE with targeted therapy, immunotherapy, or ablation improves outcomes. Concurrently, smart embolic agents are transforming TACE from passive embolization into active modulation of the tumor microenvironment. This review systematically evaluates clinical evidence for TACE-based combinations and principles guiding individualized selection. We delineate synergistic mechanisms of TACE with systemic and locoregional therapies, and highlight functional design of novel embolic materials. Although some triplet regimens have shown progression-free survival benefits, overall survival superiority remains unproven, as exemplified by the negative OS outcome in the LEAP-012 trial. However, the available network meta-analyses are constrained by substantial heterogeneity in study design, TACE protocols, and outcome definitions, warranting cautious interpretation. Finally, we propose a multidisciplinary paradigm integrating interventional radiology, diagnostic imaging, and biomaterials science. The convergence of material innovation and combination optimization holds promise for overcoming TACE’s therapeutic ceiling. Plain Language Summary: Hepatocellular carcinoma is the most common primary liver cancer. For intermediate-stage disease, TACE is standard, but its long-term effectiveness is limited because the oxygen-deprived environment it creates can stimulate tumor regrowth. Two strategies have been developed to overcome this: combining TACE with other treatments (targeted drugs, immunotherapy, ablation) and designing new smart embolic materials (hydrogels that respond to tumor conditions). This review integrates these two research directions, synthesizes evidence from clinical trials and network meta-analyses, and proposes a multidisciplinary paradigm to help clinicians and researchers develop more effective, personalized strategies. An infographic schematic titled Precision-Guided Intervention in HCC. Three labeled circles form the core: Intervention at the top, Images at the lower left and Materials at the lower right. Curved arrows connect Intervention with Images and with Materials and a curved arrow connects Images with Materials. Example items feed into the circles with arrows: TACE (liver diagram labeled liver, tumor, catheter, hepatic artery and tumor area) points to Intervention. Ablation (a probe) points to Images. Radiation therapy (cell with a target symbol) points to Images; the label Radiation therapy appears twice. On the Materials side, three sample illustrations point to Materials and the bottom label reads New Embolization Materials. A downward arrow from the central circles points to a liver illustration above the title Precision-Guided Intervention in HCC. The bottom right includes the text Created in link.Infographic of HCC precision-guided intervention linking images, materials and TACE.