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Li et al. Hepatoma Res. 2026;12:36 Page 3 of 15

supportive care and established its role as standard therapy [21,22] . Since then, technical evolution has largely
pursued three goals: higher precision, improved safety, and more consistent efficacy.

Precision and standardization of TACE
Contemporary TACE is best understood as a refined, standardized, and increasingly personalized procedure
rather than a single uniform technique . Superselective catheterization at the segmental or subsegmental
[23]
level is now widely adopted to maximize tumor devascularization while preserving functional liver
parenchyma and minimizing cumulative injury from non-target embolization . The primary objectives are
[24]
to maximize protection of normal liver parenchyma, avoiding cumulative liver damage from non-target
embolization, and to achieve complete embolization by occluding the terminal tumor vasculature. Cone-
beam computed tomography (CBCT) has become a central intra-procedural tool, providing three-
dimensional guidance for superselective delivery and enabling immediate post-embolization assessment of
coverage. On this basis, determining the embolization endpoint follows a strict individualized principle,
requiring comprehensive consideration of tumor morphology, blood supply characteristics, and the patient’s
hepatic functional reserve. The ideal endpoint is complete tumor devascularization, a hallmark of which in
conventional cTACE is the visualization of small peritumoral portal vein branches [23,25] . Furthermore, the
rational combination of differently sized embolic particles during the procedure, tailored to the vascular
anatomy, helps achieve more extensive and uniform intratumoral embolization, thereby promoting complete
necrosis.

Iterative optimization of embolic materials
Advances in embolic materials have progressed from mechanical occlusion toward engineered systems
designed for controllable drug delivery and multifunctional integration. The evolution of embolic materials
began in the 1980s with the advent of iodized oil. Its subsequent refined versions, represented by ultra-stable
ethiodized oil, laid the foundation for angiography and drug delivery due to their excellent flow
characteristics and selective tumor retention capability. Drug-eluting bead TACE (DEB-TACE) represents an
innovative breakthrough in embolic materials, including drug-coated and drug-loaded microspheres (e.g.,
HepaSphere, LifePearl, TANDEM), which combine sustained embolization with controlled drug release [26-28] .
The pivotal randomized controlled trial PRECISION V demonstrated that DEB-TACE was associated with
significantly lower doxorubicin-related systemic and hepatic toxicity compared with cTACE . A meta-
[29]
analysis of patients with intermediate-stage HCC showed that DEB-TACE achieved significantly higher
complete response and disease control rates than cTACE .
[30]

Current cutting-edge research further focuses on the integration of multiple functions, with the fundamental
logic being the development of “smart” materials built upon embolic materials. The smart drug delivery
system triggered by the tumor microenvironment is one of the representative strategies. Such materials [31-33]
(e.g., temperature-and pH-sensitive hydrogels/microspheres) can passively sense unique signals in the lesion
area within the body and accordingly alter their own structure or properties, thereby achieving targeted drug
release or prodrug activation at the intended site. Meanwhile, external energy-responsive materials can be
precisely activated via external energy sources (such as light, ultrasound, or magnetic fields) to achieve active
thermal, mechanical, or chemical cytotoxic effects [34-36] . Collectively, these innovations reflect a broader shift
from single-agent intra-arterial chemotherapy toward synergistic payload strategies that may include
immunomodulation, anti-angiogenic mechanisms, and localized energy-based enhancement.

THE EVOLUTION OF SYSTEMIC THERAPY
Systemic treatment for HCC has progressed from a period of limited benefit to a rapidly expanding
therapeutic field. Table 1 summarizes pivotal phase III first-line systemic therapy trials in advanced HCC.
Historically, advanced HCC relied primarily on chemotherapy and targeted agents. A pivotal SHARP trial in