Mineralized Supramolecular Microspheres with Immunoregulating Functions for Transarterial Chemoembolization Immunotherapy of Hepatocellular Carcinoma

Abstract Transcatheter arterial chemoembolization (TACE) is a pivotal therapeutic option for hepatocellular carcinoma (HCC) at intermediate or advanced stage. However, conventional TACE, which primarily relies on embolic microspheres for localized chemotherapy, suffers from limitations such as low drug‐loading efficiency, procedural complexity, and inadequate long‐term efficacy. More critically, traditional TACE does not address the immunosuppressive tumor microenvironment (TME), which contributes to tumor recurrence, metastasis, and poor prognosis. To overcome these limitations, a next‐generation therapeutic strategy termed transarterial chemoembolization immunotherapy (TACE‐I) is proposed, which integrates metabolic and immune modulation into the TACE framework to achieve both local tumor destruction and systemic immune activation. This is enabled by engineering supramolecular microspheres with enhanced functionality. Utilizing cyclodextrin‐based host‒guest chemistry, sorafenib is loaded into porous microspheres, which are further co‐mineralized with manganese (Mn) and dichloroacetate (DCA), affording multifunctional supramolecular microspheres (Mn‐DCA‐sora‐MS) to improve TACE‐I efficacy. These microspheres deliver sorafenib for chemotherapeutic and embolic effects, while Mn and DCA synergistically activate the cGAS–STING pathway and suppress glycolysis‐derived lactate, thereby reversing immune suppression in the TME. In vivo, Mn‐DCA‐sora‐MS largely suppresses tumor growth and metastasis in both Hepa1‐6 murine and VX2 orthotopic rabbit HCC models. Altogether, this study presents TACE‐I as a novel and distinct evolution of TACE, in which local embolization is coupled with metabolic reprogramming and immunotherapy to synergistically improve treatment outcomes for advanced HCC.