A therapeutic strategy integrating ultrasound-guided microwave ablation with nanocomposite hydrogels to enhance autophagy and suppress tumor growth in hepatocellular carcinoma

Microwave ablation (MWA) is widely recognized as an effective radical therapy for hepatocellular carcinoma (HCC). However, local ablation often results in a high risk of tumor recurrence. To address this challenge, we developed an effective anticancer drug delivery system comprising arsenic trioxide (As₂O₃)-loaded polyethylene glycol-dipalmitoylphosphatidylethanolamine (mPEG-DPPE) calcium phosphate nanoparticles (As₂O₃NPs) encapsulated within an injectable thermoresponsive hydrogel (ANPs-Gel). This study evaluated the therapeutic efficacy of MWA combined with ANPs-Gel in a rabbit hepatic VX2 tumor model. Ultrasound (US) and contrast-enhanced ultrasound (CEUS) were employed to assess tumor response and angiogenesis following treatment. The results demonstrated that MWA combined with ANPs-Gel significantly enhanced antitumor efficacy compared to other treatments, effectively inhibiting tumor growth and angiogenesis. Mechanistically, the therapeutic effects were associated with autophagy induced by MWA+ANPs-Gel, which played a critical role in promoting tumor cell death and suppressing epithelial-mesenchymal transition (EMT) both in vitro and in vivo. In vivo experiments further highlighted that the injectable thermoresponsive hydrogel system not only prolonged drug retention at the tumor site but also enhanced therapeutic efficacy by reducing EMT and preventing tumor recurrence. These findings suggest that MWA combined with ANPs-Gel provides a promising strategy for improving treatment outcomes in HCC through ultrasound-guided chemotherapy and targeted autophagy modulation. STATEMENT OF SIGNIFICANCE: This study introduces a potent therapeutic strategy that integrates ultrasound-guided microwave ablation (MWA) with a nanocomposite hydrogel to enhance autophagy and suppress tumor growth in hepatocellular carcinoma, as demonstrated in the rabbit VX2 hepatic tumor model. By combining advanced ultrasound guidance with a sophisticated nanomaterial platform, this approach significantly improves the efficacy of localized cancer therapy. Unlike conventional treatments, it not only ablates tumor cells but also regulates key cellular processes, such as autophagy, to amplify therapeutic outcomes. This work repurposes arsenic trioxide (Arsenic Trioxide) within a nanocomposite hydrogel delivery system and provides a detailed exploration of its therapeutic mechanisms when combined with MWA therapy. These findings pave the way for advanced clinical strategies in liver cancer management.