Injectable magnetic hydrogel induces multi-programmed cell death and deep tumor regression in magnetic hyperthermia therapy in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) remains global health concern due to complex pathogenic mechanism and lack of effective therapeutic drugs. The magnetic hyperthermia therapy (MHT) appears as the promising and safe strategy during the recent exploration of new technology for cancer treatment. Herein, we reported an injectable and magnetic-hydrogel-construct-based thermal regression agent mPEG-<i>b</i>-PLV-Fe₃O₄ Hybrids in MHT for the first time. Percutaneous thermotherapy was employed as a minimally invasive strategy for treating hepatic tumors in a rabbit model. Based on the evidence in vitro and in vivo studies, we demonstrated that mPEG-<i>b</i>-PLV-Fe₃O₄ Hybrids under magnetic field, exhibited powerful antitumor effect by inducing massive ROS accumulation, severe lipid peroxidation and damaged mitochondria, which together triggered triple forms of cell death: ferroptosis, autophagy and apoptosis. Furthermore, we revealed that mPEG-<i>b</i>-PLV-Fe₃O₄ Hybrids under magnetic field reprogramed the cysteine-glutathione metabolism by suppressing SLC7A11 expression, which aggravated redox imbalance and suppresses cell survival. The hybrids achieve outstanding therapeutic results in mouse and rabbit models. Our findings underscore that mPEG-<i>b</i>-PLV-Fe₃O₄ Hybrids under magnetic field is a promising strategy for cancer therapy by targeting the SLC7A11-cysteine-glutathione axis.