Materials Today Bio
·
2026
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IF 11
Linhao Jing,Shuaijun Zhao,Chenguang Sun,Fangfang Cui,Yaning Xia,Yupeng Shi,Weijie Wang
Immunotherapy has reshaped cancer treatment, yet its efficacy in many solid tumors remains limited by an immunosuppressive microenvironment and insufficient antigen presentation. As a central gatekeeper of antitumor immunity, the cGAS-STING pathway represents a key axis for converting tumor-intrinsic stress into productive immune priming. Here, we propose an integrated strategy that couples immunogenic tumor cell death with tumor-restricted cGAS-STING activation and adjuvant-amplified innate signaling. Cuproptosis, a recently identified copper-dependent cell-death program, can act as an endogenous trigger of tumor-intrinsic cGAS-STING activation, providing a promising avenue to link cytotoxicity with immune stimulation. We engineered a biomimetic, tumor-responsive nanoplatform (Cu-R837@CM) by co-assembling Cu 2+ with the TLR7 agonist R837 and cloaking the core with homologous tumor cell membranes to enhance tumor targeting and intratumoral retention. In vitro, Cu-R837@CM released Cu 2+ under acidic conditions, inducing glutathione depletion and ROS accumulation, promoting DLAT aggregation and mitochondrial dysfunction, increasing intracellular 2′3′-cGAMP, and activating cGAS-STING signaling. Concurrently, R837 enhanced dendritic-cell maturation and cytokine production, thereby improving antigen presentation. In vivo, Cu-R837@CM markedly inhibited tumor growth, increased CD4 + /CD8 + T-cell infiltration, and remodeled the tumor immune microenvironment toward an antitumor phenotype. Notably, combining Cu-R837@CM with PD-L1 blockade achieved complete tumor regression and significantly prolonged survival. Collectively, Cu-R837@CM offers a clinically translatable nanoadjuvant paradigm that integrates cuproptosis-driven cGAS-STING activation with TLR7 co-stimulation for hepatocellular carcinoma immunotherapy.
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Nature Metabolism
·
2026
·Vol. 8
·期 8
·1713-1729
·
IF 27.5
Deng Jiangming,Meng Wen,Yang Yuanqin,Xiao Ting,Jin Zhangliu,Wang Jing,Li Qing-xin,Xie Lingxiang,Hu Jingyi,Song Rong,Hu Yibo,Chu Yi,Li Qing,Jin Ping,Wang Zheng,Wu Irene XY,Liu Feng,Xiao Yang
The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS–microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.
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IMMUNITY
·
2026
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IF 30.6
Jiali Zhu,Lei Wang,Changjie Lin,Shuchen Bian,Xiaohan Luan,Yingying Sui,Luhang Piao,Wen Zhou
TREX1, but not other DEDDh exonucleases, restrains cyclic GMP-AMP synthase- stimulator of interferon genes (cGAS-STING) activation by cytosolic DNA. Here, we examined the mechanisms underlying this specificity. Biochemical comparison of TREX1 and TREX2 mapped TREX1’s ability to degrade dsDNA and suppress cGAS signaling to a single amino acid, R128. Metazoan TREX proteins containing an R128-equivalent functioned as double-stranded DNA (dsDNA) nucleases, often alongside cGAS-like receptors, defining an evolutionarily conserved family. Structurally, TREX1-R128 contacted the non-substrate strand to enable efficient dsDNA binding and cleavage. Examination of conserved structural features of the R128-containing TREX family further identified a substrate-sensing loop that inserted into the active-site cleft and stabilized the substrate strand. In human TREX1, a distinct auxiliary DNA-binding surface (B-site) strengthened DNA engagement and cGAS restraint independent of DNase activity, suggesting a competitive function. Autoimmune-associated TREX1 mutations mapped to TREX1-dsDNA interfaces, and mutations disrupting these interactions increased cGAS-STING signaling and antitumor immunity in murine models. Thus, a modular dsDNA-recognition architecture defines TREX1 specificity and regulation of the cGAS-STING pathway.
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Nanoscale
·
2025
·
IF 5.1
Jingxian Yang,Mengyao Chen,Ruihao Li,Yanting Sun,Pingting Ye,Kang Fang,Chunhui Wang,Shuo Shi,Chunyan Dong
The exclusion of immune cells from the tumor can limit the effectiveness of the immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through type I interferons (IFNs) production, facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased programmed death-ligand 1 (PD-L1) expression upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with STING agonist (Vadimezan, abbreviated as Vad) and PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of nanocore ensure the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration in immune effector cells, and lower tumor volume were observed in this integrating triple drug sequential therapy, which provides a promising prospect for the TNBC treatment.
研究领域:
肿瘤学
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免疫学
·
纳米医学
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MOLECULAR PHARMACEUTICS
·
2023
·
IF 4.9
Kehong Dong,Mei Zhang,Ying Liu,Xintao Gao,Xiaochen Wu,Dayong Shi,Chuanlong Guo,Jing Wang
Excessive acetaminophen (APAP) induces excess reactive oxygen species (ROS), leading to liver damage. Pterostilbene (PTE) has excellent antioxidant and anti-inflammatory activities, but poor solubility limits its biological activity. In this study, we prepared PTE-loaded Soluplus/poloxamer 188 mixed micelles (PTE-MMs), and the protective mechanism against APAP-induced liver injury was investigated. In vitro results showed that PTE-MMs protected H2O2-induced HepG2 cell proliferation inhibition, ROS accumulation, and mitochondrial membrane potential destruction. Immunofluorescence results indicated that PTE-MMs significantly inhibited H2O2-induced DNA damage and cGAS-STING pathway activation. For in vivo protection studies, PTE-MMs (25 and 50 mg/kg) were administered orally for 5 days, followed by APAP (300 mg/kg). The results showed that APAP significantly induced injury in liver histopathology as well as an increase in serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, the above characteristics of APAP-induced acute liver injury were inhibited by PTE-MMs. In addition, APAP-induced changes in the activities of antioxidant enzymes such as SOD and GSH in liver tissue were also inhibited by PTE-MMs. Immunohistochemical results showed that PTE-MMs inhibited APAP-induced DNA damage and cGAS-STING pathway activation in liver tissues. For in vivo therapeutic effect study, mice were first given APAP (300 mg/kg), followed by oral administration of PTE-MMs (50 mg/kg) for 3 days. The results showed that PTE-MMs exhibited promising therapeutic effects on APAP-induced acute liver injury. In conclusion, our study shows that the Soluplus/poloxamer 188 MM system has the potential to enhance the biological activity of PTE in the protection and therapeutic of liver injury.
研究领域:
药剂学
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肝脏病学
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分子生物学
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2025
·
IF 4.7
Tongtong Wu,Qiwen Yu,Yun Wang,Hongwei Tang,Wenzhi Guo
Background Liver ischemia/reperfusion (I/R) injury is an unavoidable complication during liver surgery, particularly in liver transplantation. Trillin exhibits anti-inflammatory, antioxidant, anti-apoptotic, and autophagy-inhibitory effects. However, Trillin has not been studied in liver I/R injury. Methods In this study, we investigated the effects of Trillin in liver I/R and AML12 hypoxia/reoxygenation (H/R) models. We assessed Trillin's impact on inflammatory responses, oxidative stress, apoptosis, and autophagy through H&E staining, serum transaminase levels (ALT, AST), cell viability assays, propidium iodide (PI) staining, MitoSOX staining, immunohistochemistry (IHC), transmission electron microscopy (TEM). Qualitative and quantitative analyses of mRNA and protein levels were performed to evaluate inflammatory cytokines, autophagy-related proteins, and the cyclic GMP-AMP synthase (cGAS) – stimulator of interferon genes (STING) pathway. Molecular docking and dynamics simulations were conducted to validate the binding and stability between Trillin and cGAS. Results Our results demonstrate that Trillin alleviates liver ischemia-reperfusion injury through the attenuation of autophagy in both in vitro and in vivo models. Additionally, Trillin could bind to cGAS and inhibit the activation of the cGAS-STING pathway. cGAS overexpression significantly reversed Trillin's protective effects in liver I/R injury and its inhibitory effects on the cGAS-STING pathway. Conclusion Trillin exerts protective effects against liver I/R injury by inhibiting the cGAS-STING pathway.
研究领域:
药理学
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肝脏病学
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分子生物学
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免疫学
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细胞生物学
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Advanced Science
·
2026
·
IF 14.1
Shuang Liang,Yiwei Tian,Feiyu Zhao,Yue Han,Kongshuo Ma,Linna Hai,Kaiqing Yun,Yueyang Zhao,Siqi Zhang,Ziyi Zhang,Yuxuan Peng,Kuan Hu,Jing Zhong,Bai Xiang,Zhaohui Wang
The cGAS-STING pathway, a critical cytosolic DNA-sensing mechanism in innate immunity, holds significant promise for cancer immunotherapy. However, conventional DNA-damaging therapies lack tumor specificity and cause damage to normal tissue. Furthermore, dendritic cells (DCs), central to the STING-mediated immune response, exhibit extrinsic immunosuppression via inhibitory receptors such as T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), which impairs DNA internalization and subsequent pathway activation. Herein, we engineered a telomere stress-induced nanoreactor composed of a pH-responsive zeolitic imidazolate framework-8 encapsulating telomerase-targeted 6-thio-2’-deoxyguanosine (6-thio-dG), with TIM-3 antibodies (αTIM-3) adsorbed onto its surface. Following accumulation in the tumor, the nanoreactor degrades within the acidic tumor microenvironment, releasing 6-thio-dG to induce tumor cell-specific telomeric DNA damage. Concurrently, the αTIM-3 blocks TIM-3 receptors on DCs, thereby enhancing their internalization of the released DNA. This dual-action strategy drives robust cGAS-STING activation, enhancing type I interferon production and DCs maturation. In murine models of immunogenic and poorly immunogenic tumors, the nanoreactor significantly suppresses tumor growth and prolongs survival. By coupling tumor-intrinsic telomere stress with DC-extrinsic checkpoint inhibition, this work establishes a precision platform for cGAS-STING pathway activation, presenting a promising therapeutic strategy for telomerase-positive malignancies.
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Advanced Healthcare Materials
·
2026
·
IF 11
Jiajia Jia,Zhitong Guan,Jiaxin Wang,Ting Fang,Jiajun Sun,Aiyang Tong,Yingzhen Fan,Ming Zhao,Dongkai Wang,Zheran Wang,Ji Li
Although cGAS-STING immunotherapy holds immense potential, its efficacy is severely compromised by pathway evasion. To overcome this, we engineered a core-shell bilayer nanobomb (M/ZIF/MnO 2 @DBCO) via a template-assisted approach, integrating MSC1094308 into ZIF-8 cores followed by MnO 2 shell deposition and DBCO functionalization. In a simulated tumor microenvironment, ZIF-8 loading accelerated Mn 2+ release from MnO 2 , increasing the cumulative release by nearly 30% within 8 h compared to pristine MnO 2 . Cellular assays demonstrated rapid bio-orthogonal targeting of azide-modified tumors, achieving lysosomal escape within 6 h postuptake. Subsequently, MnO 2 -mediated glutathione (GSH) depletion and hydroxyl radical (·OH) generation, combined with Zn 2+ induced mitochondrial oxidative stress, produced cytotoxic reactive oxygen species (ROS) that triggered immunogenic cell death. Furthermore, Mn 2+ , Zn 2+ , and dsDNA released from damaged mitochondria cooperatively activated the cGAS-STING pathway. Concurrently, MSC1094308 inhibited ESCRT-mediated negative regulation, as evidenced by a ∼0.2 decrease in the p-STING/VPS4B-RFP colocalization coefficient, confirming the blockade of cGAS-STING evasion. In vivo studies revealed that the nanoplatform profoundly stimulated antitumor immunity, increasing tumor-infiltrating cytotoxic T lymphocytes approximately 8-fold versus untreated controls after 21 days. This work establishes an integrated strategy harnessing Zn 2+ /Mn 2+ synergy, nanobomb reactivity, and ESCRT inhibition to circumvent cGAS-STING evasion, offering a promising paradigm for cancer immunotherapy.
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Advanced Science
·
2026
·
IF 14.1
Chao Wang,Chenxuan Zhao,Yesong Yao,Zhiwen Zou,Anxin Shi,Zhuo Feng,Mingkang Yang,Yue Yu,Yang Liu,Xuehui Rui,Jinhui Wu
Intracellular nucleotide imbalance between ribonucleotides and deoxyribonucleotides can trigger cytosolic mitochondrial DNA (mtDNA) release and subsequent activation of the cGAS–STING pathway. However, fluoropyrimidine-induced nucleotide imbalance is constrained by their metabolic instability. Here, we leverage ribonucleotides to amplify floxuridine (FUDR)-induced mtDNA release and cGAS–STING activation for enhanced cancer chemoimmunotherapy. We identified that cytidine monophosphate (CMP) significantly enhances FUDR-mediated activation of the mtDNA-driven cGAS–STING pathway, inducing over 300-fold upregulation of the interferon gene Ifnb1 and initiating STING-dependent antitumor immunity. Genome-wide CRISPR-Cas9 screening identified five pyrimidine-metabolizing enzymes (CMPK1, CMPK2, TYMP, UPP1, and UPP2) that are responsible for the metabolic instability of floxuridine monophosphate (FdUMP). CMP and its intracellular metabolites can metabolically block these enzymes, thereby increasing the peak intracellular concentration of FdUMP by over 500-fold and extending its half-life by more than 20-fold, which in turn promotes sustained intracellular nucleotide imbalance. To translate this mechanism into therapy, we co-encapsulated FdUMP and CMP into hybrid lipid nanoparticles (FC-NPs). FC-NPs robustly activated STING-dependent antitumor immunity, achieving remarkable therapeutic efficacy in multiple murine colorectal cancer (CRC) models. Our study not only addresses the long-standing issue of fluoropyrimidine metabolic instability but also reveals a novel ribonucleotide-mediated immunomodulatory mechanism, providing a promising strategy to potentiate chemoimmunotherapy in CRC.
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高影响因子
Nature Communications
·
2026
·
IF 18.1
Ling Xiaoting,Song Xingrui,Zhang Dapeng,Lai Weiyi,Liu Cong,Jiang Guibin,Zhao Qiang,Wang Hailin
Electrostatic landscapes within biomolecular condensates are critical regulators of their structural stability and functional plasticity. To quantitatively resolve these elusive electrical signatures, we develop a millisecond Flashing Electrophoretic Separation (msFES) platform enabling nanoliter-scale profiling of biomolecular condensates at near single-droplet resolution—with a focus on zeta potential characterization. Applying msFES to condensates formed by human cytosolic DNA sensor cGAS (hcGAS) and DNA, we unexpectedly discover an intrinsic electrostatic heterogeneity: droplets formed from identical components under identical conditions exhibit two distinct zeta-potential populations. This heterogeneity dictates differential susceptibility to TREX1, an exonuclease that selectively disassembles negatively charged droplets while sparing or amplifying positively charged assemblies, thereby potentially modulating cGAS activation. Pathogenic hcGAS variants (K432T, G303E) disrupt this electrostatic control, rendering hcGAS-DNA droplets hypersensitive to TREX1-mediated DNA degradation. msFES thus uncovers a hidden layer of charge-based regulation in phase-separated systems, potentially linking condensate biophysics to innate immune control.
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高影响因子
Cell Reports
·
2026
·Vol. 45
·期 3
·
IF 7.7
Qili Yang,Jinming Kang,Lin Li,Wan Zhang,Dahua Chen,Qinmiao Sun
While the cytosolic localization of cGAS is critical for cells to initiate immune responses and protect cells from viral infections, the activity of cGAS in the nucleus is inhibited to prevent autoimmune responses triggered by self-DNA. Therefore, the dynamically regulated distribution of cGAS in the cytosol and nucleus ensures its precise role in maintaining immune homeostasis. However, the molecular mechanism governing this spatial distribution of cGAS remains unclear. Here, we identify MSH6 as a regulator promoting cGAS nuclear localization by enhancing its association with importin-α proteins, consequently reducing cGAS condensation and activity. We further show that MSH6 attenuates antitumor immunity and that its deficiency in tumor cells leads to an effective tumor eradication by heat-inactivated modified vaccinia virus Ankara. Collectively, our results not only provide insights into understanding how cGAS activity is regulated but also suggest a therapeutic potential for treating MSH6-mutated tumors through the cGAS-mediated signaling pathway.
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JOURNAL OF CONTROLLED RELEASE
·
2026
·
IF 12.4
Qingqing Huang,Nana Feng,Xianghui Cao,Jian Xiao,Qiushi Li,Biyu Zhou,Yating Bai,Yu Zhao,Zhanzhan Zhang,Yang Liu
Breast cancer generally does not respond to immunotherapy due to its inherently low immunogenicity and insufficient coordination between innate and adaptive immune responses. Here, we demonstrated that concurrent activation of immunogenic cell death (ICD) and the cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) pathway synergistically amplifies antitumor immunity by promoting dendritic cell maturation, co-stimulatory signaling, and T cell priming. Building on these mechanistic insights, we designed a nanoparticle-based immunomodulator (nanoIM) that integrates a serum albumin-metal core with an endoplasmic reticulum (ER)-targeting polymer shell. Within the tumor microenvironment (TME), nanoIM induces ER stress-mediated ICD and simultaneously releases Mn 2+ or Zn 2+ ions to activate the cGAS–STING pathway, thereby bridging innate and adaptive immune activation. Systemic administration of nanoIM in breast cancer-bearing mice elicited potent T cell infiltration, robust tumor regression, prolonged survival, and effective prevention of metastasis and recurrence. This study uncovers the molecular crosstalk between ICD and cGAS–STING signaling and establishes a nanomaterial-based strategy for durable and systemic immune activation in breast cancer immunotherapy.
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