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Herein, monodisperse perfluorooctyl bromide (PFOB)\u2010loaded fucoidan\/gelatin microspheres (P@FGMS) with excellent oxygen\u2010carrying 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\u2010loading and sustained release. The resulting drug\u2010loaded microspheres (DMP@FGMS) largely enhanced chemotherapy sensitivity through an in\u2010outside hypoxia remodeling strategy: the supplement of exogenous O\n                    <jats:sub>2<\/jats:sub>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1002\/smll.74482","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T04:46:14Z","timestamp":1784522774000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In\u2010Outside Hypoxia Remodeling Strategy Triggers Ferroptosis to Boost TACE Therapy in Hepatocellular Carcinoma"],"prefix":"10.1002","volume":"22","author":[{"given":"Gaofeng","family":"Shu","sequence":"first","affiliation":[{"name":"Zhejiang Key Laboratory of Imaging and Interventional Medicine Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology The Fifth Affiliated Hospital of Wenzhou Medical University  Lishui China"},{"name":"Department of Radiology 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