cGAS-STING signaling plays a critical role in radiotherapy (RT)-mediated immunomodulation. However, RT alone is insufficient to sustain STING activation in tumors under a safe X-ray dose. Here, we propose a radiosensitization cooperated with cGAS stimulation strategy by engineering a core-shell structured nanosized radiosensitizer-based cGAS-STING agonist, which is constituted with the hafnium oxide (HfO) core and the manganese oxide (MnO) shell. HfO-mediated radiosensitization enhances immunogenic cell death to afford tumor associated antigens and adequate cytosolic dsDNA, while the GSH-degradable MnO sustainably releases Mn in tumors to improve the recognition sensitization of cGAS. The synchronization of sustained Mn supply with cumulative cytosolic dsDNA damage synergistically augments the cGAS-STING activation in irradiated tumors, thereby enhancing RT-triggered local and system effects when combined with an immune checkpoint inhibitor. Therefore, the synchronous radiosensitization with sustained STING activation is demonstrated as a potent immunostimulation strategy to optimize cancer radio-immuotherapy.
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http://dx.doi.org/10.1021/acsnano.3c09293 | DOI Listing |
Mol Cancer
December 2024
Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, 410013, China.
cGAS-STING pathway stands at the forefront of innate immunity and plays a critical role in regulating adaptive immune responses, making it as a key orchestrator of anti-tumor immunity. Despite the great potential, clinical outcomes with cGAS-STING activators have been disappointing due to their unfavorable in vivo fate, signaling an urgent need for innovative solutions to bridge the gap in clinical translation. Recent advancements in nanotechnology have propelled cGAS-STING-targeting nanomedicines to the cutting-edge of cancer therapy, leveraging precise drug delivery systems and multifunctional platforms to achieve remarkable region-specific biodistribution and potent therapeutic efficacy.
View Article and Find Full Text PDFJ Adv Res
December 2024
Department of Pathology, Xuzhou Medical University, Xuzhou, China. Electronic address:
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway has been identified as a crucial mechanism in antiviral defense and innate immunity pathway. Ferroptosis, characterized by iron dependence and lipid peroxidation, represents a specialized form of cell death. A burgeoning collection of studies has demonstrated that the cGAS-STING signaling pathway participates in the homeostatic regulation of the organism by modulating ferroptosis-associated enzyme activity or gene expression.
View Article and Find Full Text PDFInt Immunopharmacol
December 2024
Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. Electronic address:
Acute kidney injury (AKI) is a critical clinical syndrome associated with both innate and adaptive immune responses and thus increases mortality. Nevertheless, specific therapeutics for AKI are scarce so far. Recent studies have revealed that knockout of STING alleviate AKI, suggesting that STING could be an attractive target for AKI therapy.
View Article and Find Full Text PDFCell Rep
December 2024
Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea; AUTOTAC Bio, Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul 03077, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address:
The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway.
View Article and Find Full Text PDFJ Physiol
December 2024
Department of Biochemistry & Molecular Biology, University of Chicago, Chicago, IL, USA.
Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e.
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