Author: Tao, Yu ; Li, Mingqiang ; Wang, Haixia ; Zheng, Chunxiong ; Xu, Yanteng ; Luo, Xing ; Ma, Limin ; Fang, Youqiang ; Liu, Zheng ; Lv, Shixian ; Zhou, Xiangfu ; Yuan, Qing ; Lao, Yeh-Hsing

Immunotherapy through the activation of the stimulator of interferon genes (STING) signaling pathway is increasingly recognized for its robust anti-tumor efficacy. However, the effectiveness of STING activation is often compromised by inadequate anti-tumor immunity and a scarcity of primed immune cells in the tumor microenvironment. Herein, we design and fabricate a co-axial 3D-printed scaffold integrating a non-nucleotide STING agonist, SR-717, and an AKT inhibitor, MK-2206, in its respective shell and core layers, to synergistically enhance STING activation, thereby suppressing tumor recurrence and growth. SR-717 initiates the STING activation to enhance the phosphorylation of the factors along the STING pathway, while MK-2206 concurrently inhibits the AKT phosphorylation to facilitate the TBK1 phosphorylation of the STING pathway. The sequential and sustained release of SR-717 and MK-2206 from the scaffold results in a synergistic STING activation, demonstrating substantial anti-tumor efficacy across multiple tumor models. Furthermore, the scaffold promotes the recruitment and enrichment of activated dendritic cells and M1 macrophages, subsequently stimulating anti-tumor T cell activity, thereby amplifying the immunotherapeutic effect. This precise and synergistic activation of STING by the scaffold offers promising potential in tumor immunotherapy.

27 Aug 2024·ACS Nano

Biodegradable Long-Circulating Nanoagonists Optimize Tumor-Tropism Chemo-Metalloimmunotherapy for Boosted Antitumor Immunity by Cascade cGAS-STING Pathway Activation

Article

Author: Chen, Yue ; Yao, Wenjing ; Fan, Wenpei ; Li, Hao ; Xu, Yingjie ; Zhang, Cheng

The activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) has been recognized as one of the most promising immunotherapeutic strategies to induce innate antitumor immune responses. However, it is far from effective to just activate the cGAS-STING pathway, owing to abundant immunosuppressive cells that infiltrate the tumor microenvironment (TME) to impair antitumor immunity. Here, we present the smart design of biodegradable Mn-doped mesoporous silica (MM) nanoparticles with metal-organic framework (MOF) gating and hyaluronic acid (HA)-modified erythrocyte membrane (eM) camouflaging to coload cisplatin (CDDP) and SR-717 (a STING agonist) for long-circulating tumor-tropism synergistic chemo-metalloimmunotherapy by cascade cGAS-STING activation. Once internalized by tumor cells, the acidity/redox-responsive gated MOF rapidly disintegrates to release SR-717 and exposes the dual-responsive MM to decompose with CDDP release, thus inducing damage to double-stranded DNA (dsDNA) in cancer cells. As tumor-specific antigens, these dsDNA fragments released from tumor cells can trigger cGAS-STING activation and enhance dendritic cell (DC) maturation and cytotoxic T cell (CTL) infiltration, thus giving rise to excellent therapeutic effects for efficient tumor regression. Overall, this custom-designed biodegradable long-circulating nanoagonist represents a paradigm of nanotechnology in realizing the synergistic cooperation of chemotherapy and metalloimmunotherapy based on cascade cGAS-STING activation for future oncological applications.

06 Mar 2024·NeuroReport

Alpha-lipoic acid (ALA) ameliorates early brain injury after subarachnoid hemorrhage in Sprague–Dawley (SD) rats via inhibiting STING-NLRP3 inflammatory signaling

Article

Author: Zhang, Naichong ; Li, Liuqing ; Lai, Tinghai ; Tang, Liangang ; Chen, Xiaohong ; Liu, Yongqiang ; Wang, Xiangyu ; Lin, Chunnan ; Ni, Zepeng ; He, Chunliu

Neuroinflammation is intimately associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). Alpha-lipoic acid (ALA), a disulfide antioxidant, has been shown to be neuroprotective in an in vivo model of neurological injury; however, the role of ALA in SAH has never been evaluated. In this study, the Sprague–Dawley rats SAH model was induced by endovascular perforation method. ALA was transplanted intravenously into rats, and SR-717, a stimulator of interferon genes (STING) agonist, was injected intraperitoneally. The effects of ALA on early brain injury were assayed by neurological score, hematoxylin and eosin staining and Nissl staining. Immunohistochemistry staining and Western blotting were used to analyze various proteins. ALA significantly reduced STING- NLRP3 protein expression and decreased cell death, which in turn mitigated the neurobehavioral dysfunction following SAH. Furthermore, coadministration of ALA and SR-717 promoted STING-NLRP3 signaling pathway activation following SAH, which reversed the inhibitory effect of ALA on STING-NLRP3 protein activation and increased the neurological deficits. In conclusion, ALA may be a promising therapeutic strategy for alleviating early brain injury after SAH.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	US	The Scripps Research Institute	-

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