Targeting the CRYAB/β‐Catenin Axis with an MMP‐9‐Responsive Hydrogel Disrupts CTC Clusters to Suppress Progression of Hepatocellular Carcinoma after Radiofrequency Ablation

Incomplete radiofrequency ablation (iRFA) represents a major clinical challenge in hepatocellular carcinoma (HCC) management, as residual tumors acquire enhanced metastatic potential through undefined mechanisms. Herein, we report that sublethal thermal stress upregulates the heat-responsive molecular chaperone CRYAB, which stabilizes β-catenin protein by inhibiting its ubiquitin-mediated proteasomal degradation. The CRYAB/β-catenin axis drives epithelial-mesenchymal transition (EMT) in residual HCC cells and simultaneously polarizes tumor-associated neutrophils (TANs) toward the pro-tumorigenic N2 phenotype. This dual regulation pre-programs a pro-metastatic microenvironment in situ, promotes the formation of heterotypic circulating tumor cell (CTC) clusters, and ultimately accelerates tumor recurrence and metastasis post-iRFA. To suppress this pathological cascade, we engineered a matrix metalloproteinase-9 (MMP-9)-responsive thermosensitive hydrogel system (XB@Gel) that enables localized and sustained co-delivery of the β-catenin inhibitor XAV-939 and the PD-L1 inhibitor BMS-202. 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/β-catenin axis as a key transducer of thermal stress into a pro-metastatic signaling cascade in residual HCC and establish XB@Gel as a promising multi-dimensional therapeutic strategy to combat post-iRFA progression.