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

Authors

Yi-Ming Liu, Juan Qin, Si-Yuan Wu, Xue-Zhen Zhu, Yun-Fei Cai, Pei-Yao Sun, Hao Yang, Xing-Yue Wang, Shu Li, Duo Wang, Hai-Dong Zhu

Published in

Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77933. Sep 27, 2026. Epub Sep 27, 2026.

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.

PMID:
42801704
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.

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