Tumor‐Targeted FABP5/STING Cascade Promote Radiofrequency Ablation Induced Ferroptosis and Intratumoral Immune Rewiring in Hepatocellular Carcinoma

Abstract Radiofrequency ablation (RFA) has emerged as a critical therapeutic modality for hepatocellular carcinoma (HCC). Biomimetic magnetic nanoparticles further augment RFA efficacy by enhancing targeting precision and biocompatibility. This study introduces a novel nanocarrier co‐delivery system aimed at key molecular targets in HCC to amplify ferroptosis and reprogram intratumoral immunity, thereby improving the therapeutic outcomes of RFA. The proposed nanocarrier integrates cyclic arginine‐glycine‐aspartic acid (cRGD) and red blood cell membrane (RBCM), encapsulating superparamagnetic iron oxide (SPIO) to specifically target fatty acid‐binding protein 5 (FABP5) in tumor cells. Leveraging the superparamagnetic properties of SPIO, these nanoparticles enable real‐time monitoring and tracking through MRI. In vitro heat treatment of HCC cells simulates the RFA environment, while experiments employing the ferroptosis inhibitor Lipro1 conclusively demonstrate that the nanocarrier exerts anti‐tumor effects primarily through ferroptosis induction. Additionally, the impact on immunotherapy is underscored by combining the nanocarrier with anti‐PD‐L1 monoclonal antibodies. FABP5 overexpression in HCC tissues is strongly linked to RFA response. Targeting FABP5 using co‐delivery nanocarriers significantly enhances RFA efficacy. Furthermore, FABP5 deletion potentiates RFA‐induced ferroptosis and bolsters anti‐tumor immune responses, characterized by increased infiltration of CD8+ T cells and effector memory T cells, contributing to pronounced systemic anti‐tumor effects. Mechanistically, FABP5 inhibition activates the STING/TBK1 signaling pathway and modulates TBK1 protein stability. Notably, the nanocarrier system targeting FABP5 elevates PD‐L1 expression, and the combination of RFA with anti‐PD‐L1 therapy demonstrates synergistic efficacy against HCC. In conclusion, the FABP5‐targeting nanocarrier co‐delivery system offers a promising strategy to enhance RFA effectiveness in HCC, providing a novel framework for advancing clinical treatment approaches.