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Herein, we report that sublethal thermal stress upregulates the heat\u2010responsive molecular chaperone CRYAB, which stabilizes \u03b2\u2010catenin protein by inhibiting its ubiquitin\u2010mediated proteasomal degradation. The CRYAB\/\u03b2\u2010catenin axis drives epithelial\u2010mesenchymal transition (EMT) in residual HCC cells and simultaneously polarizes tumor\u2010associated neutrophils (TANs) toward the pro\u2010tumorigenic N2 phenotype. This dual regulation pre\u2010programs a pro\u2010metastatic microenvironment in situ, promotes the formation of heterotypic circulating tumor cell (CTC) clusters, and ultimately accelerates tumor recurrence and metastasis post\u2010iRFA. To suppress this pathological cascade, we engineered a matrix metalloproteinase\u20109 (MMP\u20109)\u2010responsive thermosensitive hydrogel system (XB@Gel) that enables localized and sustained co\u2010delivery of the \u03b2\u2010catenin inhibitor XAV\u2010939 and the PD\u2010L1 inhibitor BMS\u2010202. XB@Gel effectively reverses EMT, reprograms the immunosuppressive microenvironment, reduces CTC clusters, and robustly inhibits HCC recurrence and metastasis after iRFA. Collectively, our findings identify the CRYAB\/\u03b2\u2010catenin axis as a key transducer of thermal stress into a pro\u2010metastatic signaling cascade in residual HCC and establish XB@Gel as a promising multi\u2010dimensional therapeutic strategy to combat post\u2010iRFA progression.<\/jats:p>","DOI":"10.1002\/advs.77578","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:39:06Z","timestamp":1789623546000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the CRYAB\/\u03b2\u2010Catenin Axis with an MMP\u20109\u2010Responsive Hydrogel Disrupts CTC Clusters to Suppress Progression of Hepatocellular Carcinoma after Radiofrequency Ablation"],"prefix":"10.1002","author":[{"given":"Hui","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"},{"name":"Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong\u2010Hong Kong\u2010Macao University Joint Laboratory of Interventional Medicine the Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danni","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"},{"name":"Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong\u2010Hong Kong\u2010Macao University Joint Laboratory of Interventional Medicine the Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songying","family":"Pi","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"},{"name":"Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong\u2010Hong Kong\u2010Macao University Joint Laboratory of Interventional Medicine the Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongbin","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"},{"name":"Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong\u2010Hong Kong\u2010Macao University Joint Laboratory of Interventional Medicine the Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8589-982X","authenticated-orcid":false,"given":"Feile","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"},{"name":"Guangdong Provincial Engineering Research Center of Molecular Imaging Guangdong\u2010Hong Kong\u2010Macao University Joint Laboratory of Interventional Medicine the Fifth Affiliated Hospital Sun Yat\u2010sen University  Zhuhai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7281-7357","authenticated-orcid":false,"given":"Zhongzhen","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-5773-1716","authenticated-orcid":false,"given":"Yongquan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Ultrasound The Fifth Affiliated Hospital of Sun Yat\u2010Sen University  Zhuhai Guangdong Province China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"12","article-title":"Cancer Statistics, 2024","volume":"74","author":"Siegel R. 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