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Page 2 of 17 Li et al. Hepatoma Res. 2025;11:25 https://dx.doi.org/10.20517/2394-5079.2025.63

INTRODUCTION
Locoregional therapies, particularly imaging-guided liver tumor-directed procedures, are crucial in
[1,2]
managing 50%-60% of hepatocellular carcinoma (HCC) cases . Thermal ablation, such as radiofrequency
ablation (RFA) and microwave ablation (MWA), has become a standard treatment for early-stage HCC,
especially in patients with compromised liver function, due to its repeatability, simplicity, and low
[3,4]
complication rates . However, the 5-year recurrence rate remains above 50%, often due to insufficient
[5]
[6]
ablation . Residual tumors frequently exhibit rapid post-treatment growth .
Studies indicate that sublethal thermal exposure from insufficient ablation triggers autophagy and epithelial-
mesenchymal transition (EMT), thereby accelerating tumor progression . Additionally, the hypoxic and
[7,8]
immunosuppressive microenvironment that follows supports the survival and proliferation of residual
tumor cells, promoting recurrence [9,10] . In this context, accurate tumor evaluation is essential. Imaging
techniques such as contrast-enhanced ultrasound (CEUS) and computed tomography (CT) hepatic
arteriography (CTHA) play a critical role in assessing tumor infiltration and detecting satellite lesions,
facilitating more precise treatment planning [11,12] . Moreover, adjuvant therapies that combine ablation with
modalities such as radiotherapy, targeted therapy, or immunotherapy show promise in reducing post-
ablation recurrence . However, many HCC patients with underlying liver dysfunction exhibit limited
[13]
tolerance for aggressive adjuvant regimens. In addition, key challenges - including optimal regimen design,
efficacy prediction, and understanding mechanisms of resistance - require further validation through large-
scale, multicenter clinical trials.

In recent years, the emergence of nanomedicine has offered new opportunities for enhancing the efficacy of
thermal ablation-based combination treatments. Nanocarriers enable multifunctional and precise drug
delivery, potentially amplifying local therapeutic effects [14,15] . Our team previously developed a “macrophage
hitchhiking” system (MAMH) for delivering drug-loaded macrophages to ablated HCC tissue. This method
leverages the natural tropism of macrophages for post-ablation inflammatory gradients, increasing local
drug concentration nearly 10-fold, with significant tumor suppression observed in mouse and rabbit models
and favorable safety profiles . However, clinical translation of nanomedicine still necessitates extensive
[16]
systematic preclinical investigations and rigorous clinical trials for validation and optimization.

Considering these advances, we provide the first comprehensive review of the mechanisms behind tumor
progression following thermal ablation for HCC and discuss effective countermeasures, with the aim of
providing valuable insights for clinical practice.

OVERVIEW OF INSUFFICIENT ABLATION IN HCC
Thermal ablation, guided by imaging modalities such as ultrasound or CT, employs electrode needles to
emit radiofrequency currents or microwaves, generating high temperatures between 60 and 100 °C within
the tumor tissue, thereby inducing tumor necrosis . Narrowly defined, insufficient ablation is identified as
[17]
arterial-phase enhancement within the ablation zone one month post-procedure, detected by dynamic
contrast-enhanced magnetic resonance imaging (MRI) or CEUS, suggesting residual tumor tissue . More
[5]
broadly, insufficient ablation encompasses any residual tumor cells after ablation, including microsatellite
lesions and vascular infiltration, which are key contributors to tumor recurrence .
[18]

Key risk factors for insufficient ablation include large or multifocal tumors, irregular shapes, unclear
boundaries, and proximity to vital organs and major blood vessels [Figure 1]. For larger tumors, multi-
[19]
point thermal field ablation may leave blind spots due to vaporization during tissue carbonization,
increasing the risk of incomplete treatment . Irregularly shaped or poorly defined tumors are also
[20]