IMMUNITY
·
2023
·
IF 32.4
Yanfei Hou,Zhimeng Wang,Peiyuan Liu,Xubiao Wei,Zhengyin Zhang,Shilong Fan,Lulu Zhang,Fangping Han,Yikang Song,Ling Chu,Conggang Zhang
Lipid metabolism has been associated with the cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) stimulator of interferon genes (STING) DNA-sensing pathway, but our understanding of how these signals are integrated into a cohesive immunometabolic program is lacking. Here, we have identified liver X receptor (LXR) agonists as potent inhibitors of STING signaling. We show that stimulation of lipid metabolism by LXR agonists specifically suppressed cyclic GMP-AMP (cGAMP)-STING signaling. Moreover, we developed cyclic dinucleotide-conjugated beads to biochemically isolate host effectors for cGAMP inhibition, and we found that LXR ligands stimulated the expression of sphingomyelin phosphodiesterase acid-like 3A (SMPDL3A), which is a 2′3′-cGAMP-degrading enzyme. Results of crystal structures suggest that cGAMP analog induces dimerization of SMPDL3A, and the dimerization is critical for cGAMP degradation. Additionally, we have provided evidence that SMPDL3A cleaves cGAMP to restrict STING signaling in cell culture and mouse models. Our results reveal SMPDL3A as a cGAMP-specific nuclease and demonstrate a mechanism for how LXR-associated lipid metabolism modulates STING-mediated innate immunity.
研究领域:
免疫学
·
代谢
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2025
·
IF 26.3
Zhimeng Wang,Yanfei Hou,Peiyuan Liu,Ruinan Wu,Jiaming Yang,Shilong Fan,Zexu Peng,Xiaoxu Han,Bin Su,Conggang Zhang
The cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-cyclic GMP-AMP (cGAMP)-stimulator of interferon genes (STING) pathway mediates antiviral innate immunity upon sensing cytosolic DNA. Here, we examined the impact of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a paralog of the LXR lipid metabolism-induced cGAMP-degrading enzyme SMPDL3A, on viral infection. We found that SMPDL3B was induced and stabilized by both viral infection and membrane-disturbing agents, suggesting a role in sensing membrane stress as an early signal of cellular danger. Deletion of SMPDL3B impaired DNA virus infection. Upon induction, SMPDL3B suppressed cGAS-STING signaling and downstream transcriptional pathways, including the interferon response. Mechanistically, SMPDL3B functioned as a cGAMP hydrolase; cGAMP-induced SMPDL3B dimerization enabled its hydrolase activity and a negative feedback loop that dampened STING signaling. SMPDL3B-deficient cells had elevated cGAMP concentrations, and Smpdl3b −/− mice exhibited enhanced cGAMP accumulation, heightened immune activation, and reduced viral loads upon herpes simplex virus type 1 (HSV-1) infection. Thus, SMPDL3B links membrane stress to modulation of cGAS-STING signaling through cGAMP degradation, with potential implications in the contexts of inflammation or autoimmunity.
研究领域:
免疫学
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病毒学
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细胞生物学
·
先天免疫
·
信号转导
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2025
·
IF 9.6
Hua Chai,Renpeng Xia,Nan Ouyang,Jingyu Yao,Jiukun Hu,Minxuan Sun,Peng Miao
Reactive oxygen species (ROS) mediated cell damage is one of the most popular and effective ways for cancer therapy. However, overexpressed antioxidant of reduced glutathione (GSH) is always activated in tumor cells, which maintains redox equilibrium. Attempts to deplete GSH and elevate ROS levels can be potent therapeutic strategies. Herein, tumor cell membrane-encapsulated Fe 3 O 4 @MnO and 2′,3′-cyclic GMP-AMP (cGAMP) are prepared as the nanocatalyst for cancer therapy. The ionized Fe 3+ /Fe 2+ redox couple is utilized to initiate the Fenton reaction. Intracellular GSH level can thus be efficaciously controlled, and peroxide oxidation is catalyzed to produce excessive ROS. Meanwhile, cGAMP is released to trigger the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling axis. This targeted activation enhances the recruitment of macrophages, stimulates the secretion of critical pro-inflammatory cytokines, and consequently bolsters the efficacy of innate immune responses within the tumor microenvironment.
研究领域:
肿瘤学
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免疫学
·
纳米医学
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产品关联
DOI
PubMed
高影响因子
IMMUNITY
·
2021
·
IF 31.745
Run Fang,Qifei Jiang,Yukun Guan,Pengfei Gao,Rui Zhang,Zhen Zhao,Zhengfan Jiang
Summary Activation of the cyclic guanosine monophosphate (GMP)-AMP (cGAMP) sensor STING requires its translocation from the endoplasmic reticulum to the Golgi apparatus and subsequent polymerization. Using a genome-wide CRISPR-Cas9 screen to define factors critical for STING activation in cells, we identified proteins critical for biosynthesis of sulfated glycosaminoglycans (sGAGs) in the Golgi apparatus. Binding of sGAGs promoted STING polymerization through luminal, positively charged, polar residues. These residues are evolutionarily conserved, and selective mutation of specific residues inhibited STING activation. Purified or chemically synthesized sGAGs induced STING polymerization and activation of the kinase TBK1. The chain length and O -linked sulfation of sGAGs directly affected the level of STING polymerization and, therefore, its activation. Reducing the expression of Slc35b2 to inhibit GAG sulfation in mice impaired responses to vaccinia virus infection. Thus, sGAGs in the Golgi apparatus are necessary and sufficient to drive STING polymerization, providing a mechanistic understanding of the requirement for endoplasmic reticulum (ER)-to-Golgi apparatus translocation for STING activation.
研究领域:
免疫学
·
细胞生物学
·
分子生物学
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DOI
PubMed
高影响因子
JOURNAL OF IMMUNOLOGY
·
2024
·
IF 3.6
Wang Li,Cao Limin,Li Zhihong,Shao Zhugui,Chen Xia,Huang Zhicheng,He Xiaoxiao,Zheng Junke,Liu Li,Jia Xin-Ming,Xiao Hui
The cyclic GMP-AMP synthase (cGAS)–stimulator of IFN genes (STING) pathway is instrumental to antitumor immunity, yet the underlying molecular and cellular mechanisms are complex and still unfolding. A new paradigm suggests that cancer cells’ cGAS-synthesized cGAMP can be transferred to tumor-infiltrating immune cells, eliciting STING-dependent IFN-β response for antitumor immunity. Nevertheless, how the tumor microenvironment may shape this process remains unclear. In this study, we found that extracellular ATP, an immune regulatory molecule widely present in the tumor microenvironment, can potentiate cGAMP transfer, thereby boosting the STING signaling and IFN-β response in murine macrophages and fibroblasts. Notably, genetic ablation or chemical inhibition of murine volume-regulation anion channel LRRC8/volume-regulated anion channel (VRAC), a recently identified cGAMP transporter, abolished ATP-potentiated cGAMP transfer and STING-dependent IFN-β response, revealing a crucial role of LRRC8/VRAC in the cross-talk of extracellular ATP and cGAMP. Mechanistically, ATP activation of the P2X family receptors triggered Ca2+ influx and K+ efflux, promoting reactive oxygen species production. Moreover, ATP-evoked K+ efflux alleviated the phosphorylation of VRAC’s obligate subunit LRRC8A/SWELL1 on S174. Mutagenesis studies indicated that the phosphorylation of S174 on LRRC8A could act as a checkpoint for VRAC in the steady state and a rheostat of ATP responsiveness. In an MC38-transplanted tumor model, systemically blocking CD39 and ENPP1, hydroxylases of extracellular ATP and cGAMP, respectively, elevated antitumor NK, NKT, and CD8+ T cell responses and restrained tumor growth in mice. Altogether, this study establishes a crucial role of ATP in facilitating LRRC8/VRAC transport cGAMP in the tumor microenvironment and provides new insight into harnessing cGAMP transfer for antitumor immunity.
研究领域:
免疫学
·
癌症生物学
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细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR CELL
·
2023
·
IF 16
Sheng Liu,Bo Yang,Yingxiang Hou,Kaige Cui,Xiaozhu Yang,Xiaoxiong Li,Lianwan Chen,Shichao Liu,Zhichao Zhang,Yuanyuan Jia,Yufeng Xie,Ying Xue,Xiaomei Li,Bingxue Yan,Changxin Wu,Wen Deng,Jianxun Qi,Defen Lu,George F. Gao,Peiyi Wang,Guijun Shang
Summary 2′,3′-cGAMP, produced by the DNA sensor cGAS, activates stimulator of interferon genes (STING) and triggers immune response during infection. Tremendous effort has been placed on unraveling the mechanism of STING activation. However, little is known about STING inhibition. Here, we found that apo-STING exhibits a bilayer with head-to-head as well as side-by-side packing, mediated by its ligand-binding domain (LBD). This type of assembly holds two endoplasmic reticulum (ER) membranes together not only to prevent STING ER exit but also to eliminate the recruitment of TBK1, representing the autoinhibited state of STING. Additionally, we obtained the filament structure of the STING/2′,3′-cGAMP complex, which adopts a bent monolayer assembly mediated by LBD and transmembrane domain (TMD). The active, curved STING polymer could deform ER membrane to support its ER exit and anterograde transportation. Our data together provide a panoramic vision regarding STING autoinhibition and activation, which adds substantially to current understanding of the cGAS-STING pathway.
研究领域:
免疫学
·
细胞生物学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2026
·
IF 7.3
Xiang Yu,Xiaoyao Hao,Mingjiu Chen,Huricha Baigude
Therapeutic targeting of the CD47-SIRPα axis has emerged as a pivotal strategy for enhancing phagocytic clearance of tumor cells and overcoming immune evasion in solid malignancies, yet clinical outcomes with single-agent checkpoint blockade remain suboptimal due to limited activation of innate immunity and on-target toxicities. Administration of STING agonists is hampered by poor pharmacokinetics and nonspecific toxicity, highlighting the need for cell-selective delivery systems that can orchestrate immune activation and checkpoint inhibition. Herein, we conjugated cGAMP to an anti-SIRPα antibody, aiming to effectively reprogram the tumor immune microenvironment. Systemic administration of anti-SIRPα-cGAMP conjugate significantly inhibited tumor growth in a mouse model of colon adenocarcinoma and improved survival in vivo by simultaneously blocking the CD47-SIRPα “do not eat me” checkpoint and selectively delivering the STING agonist to myeloid cells. These findings suggest that targeted immunostimulatory ADCs may be an effective strategy for overcoming immune resistance in solid tumors.
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DOI
PubMed
高影响因子
Science Immunology
·
2025
·Vol. 10
·期 108
·
IF 16.3
Limin Cao,Li Wang,Zhihong Li,Xia Wei,Jinqiu Ding,Chun Zhou,Xia Chen,Zhicheng Huang,Zhugui Shao,Junchen Shen,Hongfei Lou,Keqing Zhao,Yuwei Huang,Yuanqin Yang,Han Liu,Yumeng Sun,Junling Niu,Shan Jiang,Rong Lu,Longhai Tang,Xiaoming Zhang,Haibing Zhang,Yichuan Xiao,Jianfeng Chen,Shixin Ma,Chengjiang Gao,Guangxun Meng,Li Liu,Zhaozhu Qiu,Haopeng Wang,Liufu Deng,Youqiong Ye,Xin-Ming Jia,Huabin Li,Hui Xiao
The volume-regulated anion channels (VRACs) transport osmolytes, neurotransmitters, and cyclic GMP-AMP (cGAMP) across the cell membrane to regulate cell volume and host defense. We report that the leucine-rich repeat–containing 8A/C (LRRC8A/C) VRAC plays a crucial role in immune responses to radiotherapy and chemotherapy for cancer. VRACs transfer cGAMP from irradiated cancer cells to infiltrating CD4 and CD8 T cells, thus enhancing their effector functions. TCR signaling acts as a physiological signal to open the VRAC pore through phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and reactive oxygen species (ROS). This allows the rapid uptake of cGAMP and STING activation in mouse and human T cells and induction of interferon-α/β, which up-regulate granzymes and IFN-γ in CD8 T cells. Inhibition of the extracellular hydroxylases CD39 and ENPP1 maintains extracellular ATP and cGAMP, which promotes VRAC-enhanced CD8 T cell anticancer function. Thus, the transfer of cGAMP to T cells by VRACs may be a strategy that can be targeted in future cancer therapies.
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2026
·Vol. 45
·期 4
·
IF 7.7
Yun Lv,Sheng Liu,Qihai Wang,Jing Zhu,Yingxiang Hou,Haiyan Xu,Deyan Zhu,Yu Liu,Jing Wu,Changxin Wu,Guijun Shang,Hongxiang Lou,Defen Lu,Huiqing Yuan,Deyu Zhu
The cyclic-oligonucleotide-based antiphage signaling system (CBASS) protects bacteria from phage infection. In Vibrio cholerae , phage infection activates CD-NTase DncV to produce 3′3′-cGAMP, which triggers phospholipase CapV to degrade phosphatidylethanolamine and phosphatidylglycerol, the major phospholipids in the inner-membranes, thereby inducing cell death. However, how 3′3′-cGAMP activates CapV was unclear. Here we present crystal structures of inactive Acinetobacter baumannii CapV in apo and 3′3′-cGAMP-bound forms, along with cryo-EM structures of activated CapV-3′3′-cGAMP complex, with or without substrate dioleoylphosphatidyl-ethanolamine (DOPE). Apo-CapV forms symmetric dimers in a “closed” state. 3′3′-cGAMP binding drives lateral polymerization of dimers into filament assembly, inducing an “open” state that exposes the active site and substrate-binding cleft. DOPE binding further shifts CapV to an “ajar” state, where a Y-shaped cleft positions DOPE for hydrolysis via a conserved Ser/Asp catalytic dyad. This 3′3′-cGAMP-induced filamentation mirrors activation mechanisms of TIR-STING, TIR-SAVED, and mammalian STING, revealing a conserved signaling pattern across immune systems.
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DOI
PubMed
高影响因子
JOURNAL OF CONTROLLED RELEASE
·
2022
·
IF 11.467
Hong Liu,Zhitao Hu,Haolin Chen,Yanzi Yan,Zhicheng Le,Cong Wei,Wenqiang Cao,Tianfeng Chen,Yongming Chen,Lixin Liu
Vaccination with subunit nanovaccines is a promising strategy to combat virus infection and tumor development. However, immunogenicity of present nanovaccines is still unsatisfied for clinical translation. Here, we developed a nanovaccine loading a STING agonist, 2′3′-cGAMP and, a model subunit antigen, OVA , by using a well-defined self-degradable poly(β-amino ester)s to treat B16F10-OVA melanoma tumors. The polymer underwent slow hydrolysis at pH 5.5 but self-degraded induced by the amino groups along the polyester chain at pH > 6.5. It is shown that the self-degradation products facilitated the release of 2′3′-cGAMP and OVA from early endolysome to the cytosol, where the two components strongly activated CD8 + T lymphocytes (CTLs) and significantly enhanced Ifn1, TNF , Cxcl9, and Cxcl10 expression. In turn, the tumor microenvironment was remolded from cold to hot. Moreover, the nanovaccine could be quickly drained to sentinel lymph nodes after intratumoral injection. The nanovaccine with strong immunogenicity also could reduce the side effects of systemic inflammatory reaction caused by molecular 2′3′-cGAMP. The tumor progression of animals was inhibited, and their survival rates increased significantly. Thus, the multifunctional biodegradable material provided a new delivery system for a cancer vaccine to translate to clinics.
研究领域:
癌症研究
·
免疫学
·
生物医学工程
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
ACS Nano
·
2024
·
IF 15.8
Zhao Wang,Fenglin Miao,Lingwei Gu,Ruyi Zhang,Yuan Ma,Ying Li,Jialiang Zheng,Zhenhang Lin,Yilai Gao,Liyong Huang,Ye Shen,Ting Wu,Fanghong Luo,Wengang Li
Fibrosarcoma, a malignant mesenchymal tumor, is characterized by aggressive invasiveness and a high recurrence rate, leading to poor prognosis. Anthracycline drugs, such as doxorubicin (DOX), represent the frontline chemotherapy for fibrosarcoma, but often exhibit suboptimal efficacy. Recently, exploiting the stimulator of interferon genes (STING)-mediated innate immunity has emerged as a hopeful strategy for cancer treatment. Integrating chemotherapy with immunomodulators in chemo-immunotherapy has shown potential for enhancing treatment outcomes. Herein, we introduce an advanced dendritic cell (DC) nanovaccine, cGAMP@PLGA@CRTM (GP@CRTM), combined with low-dose DOX to enhance fibrosarcoma chemo-immunotherapy. The nanovaccine consists of poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating the STING agonist 2,3-cGAMP (cGAMP@PLGA, GP) as its core, and a calreticulin (CRT) high-expressing fibrosarcoma cell membrane (CRTM) as the shell. Exposing CRT on the vaccine surface aids in recruiting DCs and stimulating uptake, facilitating efficient simultaneous delivery of STING agonists and tumor antigens to DCs. This dual delivery method effectively activates the STING pathway in DCs, triggering sustained immune stimulation. Simultaneously, low-dose DOX reduces chemotherapy-related side effects, directly kills a subset of tumor cells, and increases tumor immunogenicity, thus further amplifying immune therapeutic performance. Hence, these findings demonstrate the potential of DC nanovaccine GP@CRTM as a booster for chemotherapy. Synergistically combining low-dose DOX with the DC nanovaccine emerges as a powerful chemo-immunotherapy strategy, optimizing systemic fibrosarcoma therapy.
研究领域:
肿瘤学
·
免疫学
·
药学
·
纳米技术
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产品关联
DOI
PubMed
高影响因子
Cell Reports
·
2023
·
IF 8.8
Yingqi Liu,Xuemei Yao,Youbo Zhao,De Fang,Lei Shi,Li Yang,Guanbin Song,Kaiyong Cai,Liqi Li,Qin Deng,Menghuan Li,Zhong Luo
The tumor microenvironment (TME) plays decisive roles in disabling T cell-mediated antitumor immunity, but the immunoregulatory functions of its biophysical properties remain elusive. Extracellular matrix (ECM) stiffening is a hallmark of solid tumors. Here, we report that the stiffened ECM contributes to the immunosuppression in TME via activating the Rho-associated coiled-coil-containing protein kinase (ROCK)-myosin IIA-filamentous actin (F-actin) mechanosignaling pathway in tumor cells to promote the generation of TRIM14-scavenging nonmuscle myosin heavy chain IIA (NMHC-IIA)-F-actin stress fibers, thus accelerating the autophagic degradation of cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) to deprive tumor cyclic GMP-AMP (cGAMP) and further attenuating tumor immunogenicity. Pharmacological inhibition of myosin IIA effector molecules with blebbistatin (BLEB) or the RhoA upstream regulator of this pathway with simvastatin (SIM) restored tumor-intrinsic cGAS-mediated cGAMP production and enhanced antitumor immunity. Our work identifies that ECM stiffness is an important biophysical cue to regulate tumor immunogenicity via the ROCK-myosin IIA-F-actin axis and that inhibiting this mechanosignaling pathway could boost immunotherapeutic efficacy for effective solid tumor treatment.
研究领域:
癌症生物学
·
免疫学
·
细胞生物学
·
生物物理学
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DOI
PubMed
高影响因子
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