Glutaminolysis Blockade‐Empowered Bimodal Nanodepot for Spatially Complementary Sono‐Thermal Ablation via PANoptosis and STING Activation Against Large Tumors

ABSTRACT

Microwave ablation (MWA) for large hepatocellular carcinoma (HCC) is frequently compromised by non‐uniform thermal distribution and immunosuppressive niche formation. To address these challenges, we engineered an injectable bimodal nanodepot (TCPD) via catalytic crosslinking of dopamine‐modified hyaluronic acid by microwave thermal converter cesium‐doped Prussian blue, enabling co‐delivery of glutaminase 1 inhibitor Telaglenastat and sonosensitizer Chlorin e6. Under combined MWA and ultrasound irradiation, TCPD nanodepot disrupts cellular antioxidant defenses and bioenergetic pathways through glutaminolysis‐TCA cycle blockade, metabolically sensitizing large tumors to spatially complementary sono‐thermal ablation and enabling complete treatment coverage. This multimodal intervention induces multiple subcellular stresses, including mitochondrial and endoplasmic reticulum dysfunction, genotoxicity, and NAD ⁺ depletion, which converge to facilitate PANoptosome assembly and immunogenic PANoptosis while activating the cGAS‐STING pathway. Subsequent release of damage‐associated molecular patterns and immunoregulatory cytokines promotes dendritic cell maturation, M1 macrophage polarization, and T lymphocyte infiltration, ultimately reprogramming the immunosuppressive microenvironment toward an immune‑activated niche. Integration with anti‐PD‐1 therapy further reinvigorates cytotoxic T lymphocytes and establishes antitumor immune memory to suppress tumor progression and metastasis, offering a multimodal therapeutic strategy for large HCC.