Microwave ablation synergizes with LPS to drive abscopal tumor regression associated with ferroptosis in HCC

Hepatocellular carcinoma recurrence after microwave ablation commonly results from residual micrometastases and an immunosuppressive tumor microenvironment. To address these dual barriers, this study developed a combined strategy using ultrasound-guided microwave ablation alongside Klebsiella pneumoniae lipopolysaccharide. Through multimodal experimental approaches, the combination therapy induced interconnected therapeutic cascades: immunogenic remodeling via M1 macrophage polarization with anti-angiogenic effects; features of ferroptosis, including NRF2 suppression, glutathione depletion, and cytoplasmic lipid peroxidation; and Hsp70-mediated proteostasis counteracting copper toxicity despite modulation of the FDX1-LIAS-DLAT axis. Adaptive stress responses limited copper-dependent cell death, while prominent cytoplasmic lipid peroxide accumulation was observed spatially. This work establishes a distinctive paradigm combining localized thermal stress and macrophage reprogramming to effectively suppress post-ablation recurrence, transforming microwave ablation into a platform for systemic immunotherapy in hepatocellular carcinoma management.