Sublethal heat stress synergizes with the tumor microenvironment to drive recurrence of hepatocellular carcinoma after thermal ablation: mechanisms, molecular predictors, and targeted interventions

Although thermal ablation has emerged as a minimally invasive and effective local treatment for hepatocellular carcinoma (HCC), its high postoperative recurrence rate remains a major clinical challenge. Sublethal heat stress can induce residual tumor cells to upregulate factors such as heat shock proteins (HSPs) and hypoxia-inducible factor-1α (HIF-1α), enhancing their survival tolerance. This process synergizes with components of the tumor microenvironment (TME), including myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs), to collectively drive HCC recurrence. This article comprehensively reviews the research progress on the molecular mechanisms of tumor recurrence post-ablation, predictive biomarkers, and targeted therapeutic strategies. By deciphering multi-omics biomarkers, it provides new perspectives for predicting recurrence risk. Furthermore, this article also explores the potential of combination therapies, including targeting HSPs/HIF-1α, reversing immunosuppression, eliminating cancer stem cells (CSCs), and intervening in CAFs. This study provides a solid theoretical foundation for addressing the challenge of HCC recurrence, holding significant importance for improving patient prognosis and guiding clinical translation. Mechanisms of HCC recurrence driven by sublethal heat stress and the tumor microenvironment after thermal ablation. Sublethal heat stress generated by thermal ablation simultaneously induces intrinsic adaptive changes in residual HCC cells and remodels the extrinsic tumor microenvironment. Within the cells, stress upregulates heat shock proteins (HSPs), stabilizes hypoxia-inducible factor-1α (HIF-1α), and activates post-translational modifications (e.g., SUMOylation), thereby initiating pro-survival and signaling reprogramming. Concomitantly, stressed cells release damage-associated molecular patterns (DAMPs) and extracellular vesicles (EVs). These mediators activate cancer-associated fibroblasts (CAFs) and recruit immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs), thereby establishing an immunosuppressive niche. The remodeled microenvironment and the intrinsic adaptive processes interact continuously, collectively enriching a therapy-resistant cancer stem cell (CSC) population and activating the epithelial-mesenchymal transition (EMT) program, ultimately driving hepatocellular carcinoma (HCC) recurrence.