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.