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Page 6 of 17 Li et al. Hepatoma Res. 2025;11:25 https://dx.doi.org/10.20517/2394-5079.2025.63

(HepG2) cells upregulated pro-angiogenic PI3K/Akt/HIF-1α/vascular endothelial growth factor A (VEGFA)
signaling, with VEGF overexpression driving proliferation, migration, and CSC characteristics in residual
[37]
cells . Anti-angiogenic agents such as bevacizumab and sorafenib counter this effect. Targeting hypoxia-
related pathways may thus help mitigate recurrence risks associated with incomplete ablation. However,
tumor heterogeneity and the spatiotemporal dynamics of hypoxia complicate treatment efficacy.
Furthermore, clinical responses to anti-hypoxia and anti-angiogenic agents vary, with some patients
developing resistance, underscoring the need for further exploration of combination therapies and
biomarkers to precisely identify those who may benefit.

Immune suppression
Locoregional therapies can significantly influence the treatment outcomes of HCC by modulating the
immune microenvironment . Thermal ablation induces anti-tumor immunity by exposing antigens and
[2]
triggering immunogenic cell death. However, residual tumors from incomplete ablation create an
immunosuppressive state, accelerating progression and reducing immune checkpoint blockade (ICB)
[39]
efficacy . A major mechanism is MDSC upregulation, which is linked to postoperative recurrence .
[3]
Though ablation enhances T-cell responses to tumor-associated antigens (TAAs), these cells are suppressed
by MDSCs, with insufficient memory to prevent recurrence . Studies reveal that heat-induced METTL1
[40]
upregulates TGF-β2 translation, increasing MDSC counts, while pro-inflammatory factors from thermal
stress enhance MDSC infiltration, promoting malignancy in residual tumors [3,10] .

Tumor-associated macrophages (TAMs) also play a role; they accumulate in transitional zones post-
ablation, suggesting involvement in residual tumor progression . Mechanistically, TAMs undergo
[41]
microtubule-associated protein 1A/1B-light chain 3 (LC3)-associated phagocytosis (LAP), enabling
interleukin-4 (IL-4)-mediated reprogramming that activates the phosphoinositide 3-kinase gamma (PI3Kγ)/
AKT pathway, releasing anti-inflammatory cytokines to induce immunosuppression . Additionally,
[42]
incomplete ablation reduces antigen presentation by dendritic cells (DCs) and diminishes cytotoxic T
lymphocyte (CTL) infiltration, reinforcing the immunosuppressive microenvironment . In summary,
[15]
although incomplete ablation triggers an anti-tumor response, it also creates an immunosuppressive
environment that promotes recurrence. Overcoming this immunosuppressive microenvironment through
rational combination therapies is essential to improving ablation efficacy and reducing tumor relapse in
HCC.

STRATEGIES FOR COUNTERACTING INSUFFICIENT ABLATION
Imaging monitoring
Ablation requires complete inactivation of the tumor with adequate safety margins while minimizing
damage to normal liver tissue, demanding precise assessment of tumor infiltration and satellite lesions.
Currently guided by ultrasound and CT, thermal ablation faces limitations in intraoperative real-time
assessment. New methods aim to improve margin identification accuracy [Table 1]. Accurate imaging
evaluation enables clinicians to promptly adjust treatment strategies, thereby reducing the occurrence of
residual lesions.

CEUS reduces residual lesion incidence. In a study involving 93 patients, intraoperative CEUS identified
insufficient ablation in 34 patients (36.5%), who subsequently received additional treatment within the same
session. Twenty-four hours later, complete ablation was achieved in 88 patients (94.6%), thereby obviating
the need for secondary treatments in 29 patients (31.1%) . Due to vapor-induced artifacts, a 10-15 min
[43]
wait before CEUS assessment post-ablation is recommended . Additionally, hyperemia in ablated tissue
[44]
can complicate CEUS interpretation, which is operator-dependent. Combining CT/MRI-CEUS fusion