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

Nanomedicine shows significant potential in preventing tumor recurrence post-ablation by enhancing immune responses and anti-tumor effects through
various mechanisms. As an emerging field, its clinical indications have not yet been standardized but may include patients with insufficient ablation, poor
hepatic reserve, or intolerance to systemic therapy. In these cases, nanoplatforms can leverage the enhanced permeability and retention (EPR) effect for tumor
accumulation and remodel the immunosuppressive microenvironment, thereby inhibiting the progression of residual tumors [14,16,68] . Patient selection might
prioritize individuals with an immunosuppressive tumor microenvironment or high risk of residual disease, though this requires further validation in clinical
translation. Several preclinical studies have demonstrated its promise. For example, iRFA has been shown to enhance vascular permeability and facilitate the
accumulation of arsenic trioxide (ATO)-loaded zeolitic imidazolate framework-8 (ZIF-8) nanoparticles in residual tumors, thereby reversing EMT and
[68]
improving local control . Ao et al. designed an injectable hydrogel containing stimulator of interferon genes (STING) agonists that effectively activated the
STING pathway, increased M1 (classically activated, pro-inflammatory) macrophage polarization and cytotoxic T cell infiltration, and reversed local
[15]
immunosuppression . Xiao et al. created an antigen-capturing nanoplatform that co-delivers TAA and N6-methyladenosine (m6A) demethylase inhibitors to
tumor-infiltrating DCs (TIDCs), enhancing DC maturation and, in combination with ICB therapy, inhibiting distant tumor growth and lung metastasis .
[69]
[14]
Moreover, a Trinity nanovaccine with spatiotemporal immune effects has shown improved immune activation as an adjuvant to RFA . Cell-based micro/
nanorobots with targeted penetration, immune modulation, and precise therapy are gaining prominence in biomedical research. Our team previously
developed a “hitchhiking” technology that uses drug-loaded macrophages (MAMH) directed by ablation-induced inflammatory gradients. In this approach,
macrophage robots carrying lenvatinib accumulate in tumor tissue under these gradients, enhancing drug concentration by nearly 10-fold within lesions. This
method has shown significant tumor inhibition and favorable biosafety in mouse and rabbit models . Nanomedicine offers a multifunctional platform that
[16]
not only enables precise targeting of residual tumors but also enhances post-ablation anti-tumor responses by reshaping the immune microenvironment.
However, despite their encouraging preclinical results, most nanomedicine strategies remain far from clinical translation. Major challenges include the lack of
standardized manufacturing and characterization protocols, unpredictable biodistribution and long-term biosafety, and substantial differences between animal
models and human pathophysiology. Furthermore, immune responses to nanomaterials and scalability of production under good manufacturing practice
(GMP) conditions remain critical barriers. Future efforts should prioritize large-animal validation, comprehensive pharmacokinetic and toxicity evaluation,
and early-phase clinical trials to bridge the gap between laboratory innovation and real-world application.

Conclusion and future perspective
Thermal ablation has become a crucial therapeutic modality for HCC, particularly in patients with impaired liver function or those unsuitable for surgical
resection. Despite its minimally invasive nature and relatively high local control rates, postoperative tumor recurrence remains a significant clinical
[2,3]
challenge . The primary cause of recurrence is insufficient ablation leading to rapid progression of residual tumor cells, driven by key mechanisms such as
autophagy activation, EMT, hypoxia-induced signaling, and tumor immune evasion. These biological processes collectively establish a tumor-promoting
microenvironment around residual lesions, representing a major barrier to therapeutic efficacy [3,10,33] .