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Li et al. Hepatoma Res. 2025;11:25 https://dx.doi.org/10.20517/2394-5079.2025.63 Page 9 of 17

Thermal ablation-induced tumor necrosis generates antigens that stimulate anti-tumor immunity; however,
the resulting immunosuppressive microenvironment following insufficient ablation often drives rapid
tumor progression. As a result, combination immunotherapy has emerged as a promising strategy. A
multicenter Phase III trial (NCT00699816) found that postoperative cytokine-induced killer (CIK) cell
therapy significantly extended recurrence-free survival (RFS), with medians of 44 months in the CIK group
vs. 30 months in the control group. The CIK group also demonstrated reduced overall mortality [hazard
ratio (HR) 0.21; 95% confidence interval (CI): 0.06-0.75; P = 0.008] and cancer-related mortality (HR 0.19;
[58]
95%CI: 0.04-0.87; P = 0.02) . Emerging evidence indicates that adjuvant therapy with PD-1 inhibitors can
activate anti-tumor immune responses within the HCC microenvironment and has shown promise in
[59]
improving RFS . A retrospective study found that combining PD-1 inhibitors with RFA yielded a 1-year
[60]
RFS rate of 32.5%, compared to 10.0% for RFA alone . The IMbrave050 study (NCT04102098) randomized
high-risk HCC patients after resection or ablation into adjuvant atezolizumab-bevacizumab (atezo-bev) and
active surveillance groups, enrolling 668 patients. After a median 17.4 month follow-up, the 12 month RFS
rate was 78% in the atezo-bev group vs. 65% in the surveillance group. This is the first Phase III trial
showing improved RFS with adjuvant therapy post-curative resection or ablation, underscoring its potential
to enhance prognosis following insufficient ablation . Numerous trials exploring ablation-combination
[61]
therapies are ongoing, aiming to advance these strategies from preclinical studies into clinical practice
[Table 2].

The use of appropriate biomarkers for patient stratification is key to further improving the efficacy of
immune checkpoint inhibitors (ICIs) in HCC. However, predicting response to ICIs in HCC is highly
complex. The value of programmed death-ligand 1 (PD-L1) expression (≥ 1%) or tumor mutational burden
(TMB) as predictive biomarkers has not been clearly established . However, current research consensus
[62]
suggests that “inflamed” HCCs - which are characterized by the enrichment of three distinct gene
signatures: inflammatory, interferon-related antigen presentation, and T-cell-inflamed - are associated with
a more favorable response to ICIs. These features are posited to be predictive of ICI responsiveness . In
[63]
clinical practice, caution is warranted when considering immunotherapy for patients with chronic hepatitis
B virus (HBV) infection. HBV infection is closely linked to persistent liver inflammation and immune
exhaustion. In particular, patients who are hepatitis B surface antigen (HBsAg)-positive or have a high viral
load often exhibit severe T-cell dysfunction, which may impair their overall response to immunotherapy.
Moreover, ICI therapy itself carries a significant risk of HBV reactivation . While high-quality RCTs on
[64]
adjuvant antiviral therapy for early-stage HCC patients’ post-ablation are lacking, retrospective studies
suggest that antiviral therapy significantly reduces recurrence risk and prolongs overall survival (OS) in
HBV-related HCC patients after RFA . Future studies should incorporate HBV status into biomarker
[65]
stratification to better guide personalized treatment strategies.

Inflammatory cytokines such as interleukin (IL)-1β, IL-6, and growth factors including TGF-β and VEGF
play critical roles in tumor initiation and progression. Molecular targeted therapies aimed at these pro-
tumorigenic signaling pathways may improve patient outcomes . A multicenter retrospective study
[36]
demonstrated that adjuvant sorafenib after RFA in early-stage HCC patients significantly reduced
recurrence and prolonged OS . However, the STORM trial (NCT00692770) failed to show a significant
[66]
reduction in recurrence following curative surgery or ablation, possibly due to the lack of stratification
based on inflammatory status and the limited proportion of ablation cases included . Therefore, stratifying
[67]
patients based on inflammatory biomarkers - such as IL-6, C-reactive Protein (CRP), and VEGFA - may
enhance the efficacy of targeted adjuvant therapies. For patients with high systemic inflammation and poor
hepatic reserve, locally delivered targeted drug systems may also offer a promising alternative by
minimizing systemic toxicity.