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Ma et al. Hepatoma Res. 2026;12:43 Page 5 of 22

Table 1. Comparison of three definitions of TACE refractoriness
JSH (Japan, 2014 Update) [21] European consensus [20] CCI (China) [23]

≥ 2 consecutive insufficient responses
of treated tumor (viable lesion > 50%) Untreatable tumor progression: massive liver After ≥ 3 consecutive standardized and
despite change of chemotherapeutic involvement, extrahepatic spread, vascular precision TACE sessions, target
agents or feeding artery reanalysis invasion tumor(s) still PD by mRECIST
≥ 2 consecutive intrahepatic Impaired liver function (Child- New intrahepatic lesion(s) post-TACE
Key criteria progressions (increase in tumor Pugh)/performance status are not considered TACE refractoriness
number) ART score ≥ 2.5 (no benefit from further Macrovascular invasion or extrahepatic
Continuous elevation of tumor markers TACE) metastasis alone does not define
after TACE Stable disease or progression after two refractoriness
Appearance of vascular invasion TACE sessions is considered insufficient Emphasizes “TACE unsuitable”
Appearance of extrahepatic spread
1. Tailored to Chinese patients with a
high tumor burden and HBV background
Clear, quantifiable imaging and tumor 1. Incorporates liver function and 2. New lesions do not trigger
marker criteria performance status refractoriness, avoiding premature
Based on superselective lipiodol TACE 2. Uses ART score for objectivity TACE withdrawal
Strengths Early switch after consecutive failures 3. Fits Western patients with more advanced 3. The “six-and-twelve” score was
to preserve liver function disease at presentation introduced for better stratification in
High expert agreement in Japan 4. Clear concept of “untreatable China
(84%-96%) progression”
4. Supports combination with systemic
therapies or brachytherapy
Best suited for patients with low tumor Refractoriness requires ≥ 3 TACE
burden (common in Japan) The ART score performs poorly in low- sessions before defining, which may
“Continuous elevation” of tumor tumor-burden populations (e.g., Japan) delay treatment switch
markers not precisely defined No unified timing for imaging assessment However, it has not yet been validated
Limitations Controversy over whether stable disease
Does not fully incorporate dynamic in large multicenter prospective studies
liver function changes should be considered refractoriness No clear cutoff for tumor markers
Limited validation in Western or No clear guidance on new intrahepatic 4. Not internationally accepted outside
Chinese populations nodules China
Best suited for patients with low tumor Based on a 2020 survey of 257 Chinese
burden (common in Japan) physicians
“Continuous elevation” of tumor ART score validated in European cohorts Consensus agreed by 31 senior experts
Validation markers not precisely defined Not validated in Japanese or Chinese (2021 CCI annual congress)
status Does not fully incorporate dynamic populations No large prospective validation yet
liver function changes No direct RCT validation for the definition Considered suitable for Chinese high-
Limited validation in Western or itself tumor-burden HCC, lacking
Chinese populations international validation
HCC: Hepatocellular carcinoma; TACE: transarterial chemoembolization; JSH: Japan Society of Hepatology; CCI: the Chinese College of
Interventionalists; ART: Assessment for Retreatment; RCT: randomized controlled trial; mRECIST: modified Response Evaluation Criteria in Solid
Tumors; HBV: hepatitis B virus.

TACE is not only related to clinical treatment response but also involves complex tumor biological adaptive
changes. Previous reviews have concluded that a variety of molecular mechanisms jointly drive the
[25]
formation of TACE refractoriness, mainly involving tumor microenvironment remodeling, cell state
regulation, and metabolic reorganization. First, the hypoxic microenvironment is the most direct change
observed after TACE. It activates the Hypoxia-Inducible Factor-1α/Hypoxia-Inducible Factor-2α signaling
pathway and promotes angiogenesis, glycolysis, epithelial-mesenchymal transition, and anti-apoptosis,
thereby enhancing tumor survival. Mitochondria adapt to hypoxia through division, autophagy, and
metabolic reprogramming, further consolidating the resistance phenotype. Reactive oxygen species (ROS)
accumulation further stabilizes hypoxia-inducible factor (HIF) and activates pathways such as Nuclear
Factor Kappa B, enhancing DNA repair and chemoresistance. Second, some tumor cells may enter a
dormant state after TACE and be reactivated through cell cycle restart and epigenetic remodeling after
microenvironment improvement, leading to tumor recurrence and progression. In addition, TACE can also
aggravate the acidification of the tumor microenvironment, inhibit T cell function, promote the infiltration
of immunosuppressive cells, and directly reduce treatment efficiency by efflux of chemotherapy drugs
through proton pumps. Finally, excessive activation of autophagy mediates treatment resistance by clearing
damaged mitochondria, inhibiting apoptosis, secreting immunosuppressive exosomes, maintaining tumor
cell survival, promoting immune escape, and forming a fibrotic microenvironment. Together, these