In-Outside Hypoxia Remodeling Strategy Triggers Ferroptosis to Boost TACE Therapy in Hepatocellular Carcinoma.

The therapeutic efficacy of transarterial chemoembolization (TACE) is strongly limited by the hypoxic and immunosuppressive tumor microenvironment (TME). Herein, monodisperse perfluorooctyl bromide (PFOB)-loaded fucoidan/gelatin microspheres (P@FGMS) with excellent oxygen-carrying capability were prepared for enhanced TACE treatment of hepatocellular carcinoma (HCC). It was found that the introduction of fucoidan endowed P@FGMS with excellent electrostatic affinity for positively charged doxorubicin (DOX) and metformin (MET), enabling their efficient co-loading and sustained release. The resulting drug-loaded microspheres (DMP@FGMS) largely enhanced chemotherapy sensitivity through an in-outside hypoxia remodeling strategy: the supplement of exogenous O2 via PFOB and inhibition of intracellular oxygen consumption by MET. Notably, DMP@FGMS could not only modulate hypoxic TME, but also generate intracellular ROS and disrupt the redox homeostasis, thereby triggering cancer ferroptosis. Moreover, DMP@FGMS effectively remodeled the immunosuppressive TME by alleviating tumor hypoxia and inducing immunogenic cell death (ICD), thereby enhancing CD8+ T cell infiltration while reducing immunosuppressive cell populations. Consequently, DMP@FGMS could effectively suppress tumor growth in an orthotopic HCC rat model, with this effect further potentiated by combination with immune checkpoint blockade therapy. Therefore, this study demonstrates that DMP@FGMS is a potent embolic agent capable of remodeling the hypoxic/immunosuppressive TME, representing a promising strategy for TACE treatment of HCC.