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Page 2 of 15 Li et al. Hepatoma Res. 2026;12:36

refinements may help determine how early disease-control gains can be translated more consistently into durable
OS benefit, particularly for patients with intermediate-stage HCC.

INTRODUCTION
Hepatocellular carcinoma (HCC) continues to pose a major global health burden and is among the most
common malignancies and leading causes of cancer-related death worldwide . Although vaccination and
[1]
antiviral treatment have reduced the incidence of hepatitis B virus (HBV)-related HCC in some regions , the
[2]
burden of HCC associated with metabolic dysfunction-associated steatotic liver disease (MASLD) is
increasing . Many patients are diagnosed after the window for curative resection, or ablation has passed ,
[4]
[3]
making locoregional and systemic therapies the therapeutic backbone for many patients.

For decades, transarterial chemoembolization (TACE) has been the standard option for intermediate-stage
HCC [5-7] . However, clinical outcomes after TACE are heterogeneous, and recurrence remains common.
Mechanistically, TACE induces tumor ischemia and immunogenic cell death , but may also trigger hypoxia-
[8]
driven angiogenesis and reinforce an immunosuppressive tumor microenvironment [9,10] , thereby limiting
durable disease control. Systemic treatments, including immune checkpoint inhibitors (ICIs) and targeted
agents including anti-vascular endothelial growth factor (VEGF) antibody and tyrosine kinase inhibitors
(TKIs) - can potentially counteract these adaptive changes after TACE, providing a strong biological
rationale for combination strategies . Accordingly, multiple randomized trials have evaluated TACE in
[11]
combination with systemic therapy across different sequencing paradigms and endpoint frameworks. Recent
results from four key trials, including EMERALD-1 , LEAP-012 , TALENTACE , and CAP-ACE , have
[15]
[12]
[13]
[14]
demonstrated significant benefits in progression-free survival (PFS) and objective response rate (ORR),
accelerating guideline discussions and clinical adoption in selected settings . Nevertheless, clinicians now
[16]
face a more complex decision landscape: overall survival (OS) remains immature or not yet definitively
improved in several trials, and substantial heterogeneity persists regarding when to initiate systemic therapy
relative to TACE, how to operationalize on-demand TACE in trial protocols, and which endpoints best
reflect clinically meaningful benefit in the modern era of effective post-progression therapy.

In contrast to previous reviews that mainly summarized efficacy outcomes, this narrative review interprets
available evidence from a trial-design perspective. Relevant literature was identified through searches of
PubMed, Web of Science, Embase, and ClinicalTrials.gov up to 2025 using core terms: “HCC”, “TACE”,
“systemic therapy”, and “combination therapy”. Randomized trials, landmark studies, and major clinical
guidelines were prioritized. Trials were highlighted if they impacted clinical practice or illustrated
methodological issues critical to interpreting TACE-based combination therapy. A preliminary version of
this study has been published as a preprint .
[17]

EVOLUTION OF TACE TECHNIQUES: FROM EMPIRICAL EMBOLIZATION TO PRECISION AND
PERSONALIZED THERAPY
The development of TACE is rooted in the hemodynamic hallmark of HCC, in which tumor blood supply
progressively shifts toward the hepatic artery, whereas the non-tumoral liver parenchyma remains
predominantly portal venous . This physiological contrast enables selective intra-arterial drug delivery and
[18]
embolization to achieve a dual effect - tumor starvation and cytotoxic exposure - while limiting collateral
injury to surrounding liver tissue. Its origins can be traced to the first hepatic artery embolization performed
by Goldstein in 1976 . Subsequently, Nakakuma in the 1980s innovatively introduced gelatin sponge and
[19]
iodized oil as a mitomycin carrier, establishing the classic model of conventional TACE (cTACE) . Two
[20]
randomized trials published in 2002 subsequently demonstrated a survival advantage of TACE over