Yujia Wang,1,2,* Hongtong Tan,1,2,* Chunyong Wen,1,2 Shuanggang Chen,1,2 Guanglei Zheng,1,2 Han Qi,1,2 Lin Xie,1,2 Lujun Shen,1,2 Fei Cao,1,2 Weijun Fan1,2 

1Department of Minimally Invasive & Interventional Therapy, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China; 2State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Weijun Fan, Department of Minimally Invasive & Interventional Therapy, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Yuexiu District, Guangzhou, Guangdong, 510060, People’s Republic of China, Tel +86 138 2615 4530 ; +86-20-87343272, Fax +86-20-87343272, Email fanwj@sysucc.org.cn Fei Cao, Department of Minimally Invasive & Interventional Therapy, Sun Yat-Sen University Cancer Center, 651 Dongfeng East Road, Yuexiu District, Guangzhou, Guangdong, 510060, People’s Republic of China, +86-13480211104, Email caofei@sysucc.org.cn

Background: Microwave ablation (MWA) is commonly used to treat hepatocellular carcinoma (HCC), but its effects on normal liver tissue and tumors remain unclear. While MWA causes direct tumor destruction, it also induces inflammatory responses in the surrounding liver tissue, which may influence tumor progression, metastasis, and recurrence. The role of cytokine alterations in this post-ablation inflammatory microenvironment is crucial for understanding how MWA impacts tumor behavior.
Purpose: This study aims to investigate the impact of post-ablation inflammatory responses on HCC recurrence and metastasis through animal experiments and cytokine profiling, with the goal of identifying potential biomarkers or therapeutic targets.
Materials and Methods: This study involved 35 male C57BL/6 mice (6– 8 weeks old) to establish metastatic and orthotopic cancer models. The effects of normal liver tissue ablation and HCC ablation on tumor metastasis and recurrence were investigated. Cytokine expression changes were assessed using the Proteome Profiler Mouse XL Cytokine Array, and prognostic implications were analyzed using the TCGA database. Multiple group comparisons assessed using the Mann–Whitney U-test. Statistical significance was defined as a two-tailed p-value less than 0.05.
Results: Microwave ablation of normal liver tissue promotes intrahepatic metastasis of HCC. Incomplete ablation of liver tumors accelerates intrahepatic or pulmonary metastasis. Post-ablation, increased expression of MMP-9, OPN, VEGF, CHI3L1, AREG, CXCL2, and IL-1α in the peritumoral region suggests a shift toward a pro-inflammatory and pro-metastatic microenvironment, potentially facilitating tumor cell invasion, angiogenesis, and immune evasion.
Conclusion: HCC recurrence and metastasis following ablation may be driven by cytokine-mediated changes in the tumor microenvironment. Targeting key cytokines such as MMP-9, OPN, and CHI3L1 could provide new strategies for improving post-ablation outcomes and reducing recurrence rates in clinical settings.
Summary Statement: Microwave ablation of normal liver tissue significantly promotes metastasis of hepatocellular carcinoma in mice, accompanied by increased cytokine expression, including MMP-9 and VEGF, within the periablation microenvironment.

Keywords: hepatocellular carcinoma, microwave ablation, matrix metallopeptidase 9, tumor recurrence, inflammatory response