Lactate Homeostasis Disruption Potentiates TACE‐Immunotherapy in Hepatocellular Carcinoma

ABSTRACT

Developing strategies that simultaneously overcome chemoresistance and immune suppression remains a major challenge for improving transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Inspired by clinically used CaCO ₃ microspheres in TACE, we propose an “extracellular buffering‐intracellular metabolic disruption” strategy to precisely regulate lactate homeostasis for targeted therapy. Herein, we engineered multifunctional embolic microspheres (SDCa‐MSs) co‐loaded with calcium carbonate nanoparticles (CaNPs), syrosingopine (Syr), and doxorubicin (DOX) for TACE application. Within the acidic tumor microenvironment, SDCa‐MSs buffer extracellular acidity while disrupting intracellular lactate metabolism, thereby simultaneously remodeling extracellular and intracellular pH homeostasis. This coordinated regulation enhances DOX efficacy, induces calcium dyshomeostasis and immunogenic cell death, and ultimately stimulates robust antitumor immunity. In multiple murine HCC models, SDCa‐MSs markedly suppress tumor growth, remodel the tumor immune microenvironment, and synergistically enhance the therapeutic efficacy of anti‐PD‐L1 immunotherapy. By integrating metabolic regulation, chemotherapy, and immune activation into a single embolic platform, this work establishes an acid–base homeostasis‐regulating strategy for potentiating TACE and provides a conceptual framework for improving locoregional cancer immunotherapy.