CELL DEATH AND DIFFERENTIATION
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2026
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IF 13.6
Zhou Chen,Bai Dongsheng,Zhao Jiawei,Yin HongJie,Du Jiaying,Gu Chunyang,Wang Yuxiang,Lin Binyan,Lu Na,Zhao Yue
The cGAS-STING signaling serves as a central hub for innate immunity by orchestrating type I interferon production and inflammatory cascades in response to cytosolic DNA. A critical rate-limiting step in this pathway involves STING exit from the endoplasmic reticulum (ER), a process initiated by COPII-mediated trafficking that requires ER membrane curvature formation. However, the molecular mechanism that drives this process is poorly understood. In this study, we identify VMP1, an ER-resident transmembrane protein, as a negative regulator that constrains STING ER exit and downstream signaling activation. VMP1 controlled ER PtdIns(3)P accumulation, which was essential for ER membrane curvature formation. Depletion of Vmp1 triggered CDIPT-dependent PtdIns(3)P synthesis through a non-canonical pathway independent of VPS34 stability and MTMR3 expression. Furthermore, VMP1-mediated macroautophagy degraded Rab10 GTPase, thereby suppressing CDIPT recruitment to the ER membrane. Myeloid-specific Vmp1 knockout mice exhibited augmented antiviral defense against DNA virus infection but displayed unaltered susceptibility to RNA virus infection. These results suggest that VMP1 controls STING trafficking by modulating the Rab10-CDIPT axis to restrict ER PtdIns(3)P accumulation and limit ER membrane curvature formation required for COPII vesicle biogenesis.
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INFLAMMATION RESEARCH
·
2026
·Vol. 75
·期 1
·79
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IF 6.2
Zhao Junyong,Luo Xiaolin,Wang Zelan,Luo Wenjian,Wu Shaofa,Ma Xingyu,Liu He,Chen Yang,Pi Shixian,Zhang Jiawen,Zhang Jihang,Liu Chuan,Bi Xianjin,Qin Zhexue
Aims Vascular calcification (VC) predicts cardiovascular risk in diabetes, chronic kidney disease (CKD) and atherosclerosis patients and is closely linked to the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Our previous work revealed that cGAS-STING signalling pathway in VSMCs increases CKD-associated atherosclerotic plaque vulnerability and recent studies elucidated the involvement of STING in vascular calcification, but its upstream modulation mechanism remains to be elucidated. Methods and results DNA damage and robust upregulation of STING occurred in high phosphate (Pi)-stimulated VSMCs, calcified aortic tissues from 1,25(OH) 2 VitD 3 (VitD 3 )-overloaded mice and radial arteries from CKD patients, and these changes were accompanied by the activation of the cGAS‒STING signalling pathway. STING deficiency alleviated vascular calcification in CKD model mice. STING knockdown suppressed calcium deposition and the expression of osteogenic transdifferentiation markers in VSMCs, whereas the overexpression of STING or its agonist 2′,3′-cGAMP exacerbated VC. Mechanistically, Brd4 was identified as a critical epigenetic regulator of Pi-induced DNA damage, STING activation and VC. Furthermore, the N6-methyladenosine (m6A) modification of STING mRNA was significantly increased in Pi-stimulated VSMCs, increasing its stability. Brd4 depletion decreased the m6A modification of STING and accelerated its degradation. The m6A modification of STING was mediated by the core methyltransferase Mettl3, whose transcription was regulated by Brd4. Finally, C-176 showed translational potential by effectively suppressing vascular calcification and osteogenesis markers expression in both VitD 3 -overloaded mice and Pi-stimulated VSMCs. Conclusions Our study elucidated the interplay between Brd4-mediated epigenetic and Mettl3-dependent epitranscriptomic mechanisms governs STING m6A modification and STING may be a potential therapeutic target for vascular calcification.
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MATERIALS & DESIGN
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2026
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IF 8.2
Yuanxiang Yu,Wenjing Li,Yu Shao,Hairui Tian,Tingting Deng,Meili Li,Jiarui Li,Xuanhuan Ma,Zhenhao Li,Cong Huang,Wei Jiang,Xiaoxiao Luo
A phase-change nanocomposite enables light-triggered multimodal therapy and tumor-localized cisplatin release. • Photothermal and photodynamic stress induces mitochondrial DNA damage and cytosolic DNA sensing. • Innate immune activation drives immunogenic cell death, dendritic cell priming, and CD8+ T-cell infiltration. • The treatment achieves durable control and helps overcome immune resistance in triple-negative breast cancer. Activation of the GMP/AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway can sensitize tumors to immunotherapy, yet conventional photothermal therapy (PTT) or photodynamic therapy (PDT) alone rarely generates enough cytosolic double-stranded DNA (dsDNA) to fully engage this axis. Here we develop phase-change lauric-acid nanocomposites (CCL NPs) that co-load photothermal Cu 2-X S nanoparticles and cisplatin. After cellular uptake, near-infrared (NIR) irradiation induces synergistic PTT/PDT, and NIR-II heating melts the lauric-acid shell to trigger on-demand cisplatin release within tumors. The resulting ROS burst together with cisplatin causes extensive mitochondrial DNA damage and dsDNA leakage into the cytosol, leading to robust cGAS/STING activation. In tumor-bearing mice, CCL NPs promote dendritic-cell maturation and antigen cross-presentation, increase cytotoxic T-lymphocyte infiltration, and elicit immunogenic cell death, achieving durable tumor suppression with minimal systemic toxicity. Released copper further contributes via cuproptosis. Overall, CCL NPs integrate controllable chemotherapy with PTT/PDT to amplify innate immune sensing and drive effective antitumor immunity. Download: Download high-res image (164KB) Download: Download full-size image
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CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Liang Liu,Siyu Liu,Qiaobian He,Chengxiu Sun,Yisha Li,Shengran Li,Xifei Yu
Dendrimer-functionalized LNPs provide a strategy to enhance tumor vaccine efficacy. • Choline phosphate-modified PAMAM improves biosafety and mRNA transfection efficiency. • PC7A-modified dendrimers activate STING signaling and promote DC maturation. Polyamine-based lipid nanoparticles (LNPs) are considered a highly promising strategy for tumor therapy due to their exceptional endosomal release and cytoplasmic transfection efficiency. However, the high density of amino groups in polyamine-based lipid nanoparticles leads to low biosafety and immunogenicity, resulting in suboptimal tumor efficacy. Here, we report functional components synthesized by modifying polyamide amine (PAMAM) dendrimers with choline phosphate (CP) group, linoleic acid chains (L18), and a nitrogenous heterocycles (PC7A) molecule to enhance the mRNA delivery efficiency and immunogenicity against tumors associated with standard LNPs. Incorporating functional components into LNPs enables the effective disruption of endosomal structures—while ensuring biosafety—thereby facilitating the efficient and stable delivery of antigenic mRNA. Simultaneously, PC7A, acting as an activator of interferon gene stimulating factors, promotes dendritic cells (DCs) maturation, further enhancing the immunogenicity of LNPs. After the injection of the nanovaccines into mice, the massive generation and recruitment of tumor-specific cytotoxic T cells further enhanced the efficacy of immunotherapy, providing a new strategy for the synergistic enhancement of LNP-based functional components in tumor vaccines. Modifying dendrimers with choline phosphate (CP) groups, linoleic acid (L18), and nitrogen-containing seven-membered heterocyclic molecule (PC7A) can effectively improve the performance of mRNA-LNPs. These enhancements include reduced biotoxicity, increased endosome escape, and STING pathway activation-mediated immunogenicity, which can effectively improve the efficacy of vaccines in cancer treatment. Download: Download high-res image (133KB) Download: Download full-size image
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ACTA PHARMACOLOGICA SINICA
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2025
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IF 8.4
Zhao Man,Jin Zu-yi,Fan Wei-zhen,Qiang Peng-fei,Zheng Zhi-hua,Li Guo-feng,Hong Liang,Li Min
The stimulator of interferon genes (STING) is a crucial pattern recognition receptor that activates innate immunity, particularly in response to pathogen infection and various stimuli. Notably, activation of STING exhibits remarkable potential in enhancing anti-tumor immunity, underscoring the significance of discovering STING small molecule agonists. Recently, zinc pyrithione (ZPT), a marketed antifungal small molecule, has been reported to possess anti-tumor activity through various mechanisms. Our preliminary screening of STING agonists revealed that ZPT could significantly induce STING activation. In this study, we investigated whether ZPT exerted anticancer effects as a small molecule activator of STING. We showed that ZPT bound to the STING protein in vitro with K D value of 2.72 μM, and ZPT (1–16 μM) dose-dependently activated the STING-TBK1-IRF3 signaling axis in THP-1 cells. In MC38 tumor-bearing wild-type C57BL/6 mice with normal immune systems, administration of ZPT (5, 10, or 20 mg/kg, i.p., every two days for 14 days) dose-dependently inhibited the tumor growth, activated CD45 + , CD3 + , and CD8 + T cells in both tumors and spleens, and significantly elevated IL-6 secretion in the peripheral blood. These results highlight the potential of ZPT as an immunotherapeutic agent targeting STING.
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International Journal of Pharmaceutics-X
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2025
·
IF 6.4
Mengjie Rui,Haidan Tang,Lianglai Gao,Yujiao Hu,Wenyan Liang,Yinfeng Li,Chunlai Feng
Peptides hold great promise in tumor immunotherapy, but suffer from poor stability and short systemic circulation. To overcome these challenges, we developed a pH-responsive nanodelivery systems (P-NPs) based on the amphiphilic block polymer PEO-PC7A. In addition to its role in peptide encapsulation and protection, PEO-PC7A intrinsically acted as a stimulator of the interferon genes (STING) agonist, activating the cGAS-STING signaling pathway and remodeling the immunosuppressive tumor microenvironment. P-NPs were successfully prepared via a self-assembly technique, yielding nanoparticles with a uniform diameter of 91.2 ± 3.5 nm. Their pH-responsive behavior was confirmed by significant change in particle size and accelerated peptide release under acidic conditions. In vitro , P-NPs effectively increased the cytotoxic activity of T cells and induced higher interleukin-2 (IL-2) secretion compared to free peptide. In a 4 T1 tumor-bearing mouse model, intravenous administration of P-NPs achieved greater tumor growth inhibition and higher intratumoral interferon-γ (IFN-γ) levels than free peptide, with minimal systemic toxicity and no significant impact on body weight. Overall, our study presented a novel multifunctional peptide nanocarrier that enhanced tumor immunotherapy efficacy by concurrently improving peptide delivery and stimulating innate immunity, providing a promising foundation for the further development of innovative combination cancer immunotherapy strategies.
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JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-17
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IF 12.6
Bai Ge,Liu Hongwen,Li Wei,Chen Sijia,Wang Lishan,Wang Zhangding,Zhou Yue,Pan Yani,Liu Yu,Chen Qi,Zhang Nannan,Wei Jingjing,Fu Xueni,Zhou Yaru,Zhu Yun,Xu Lei,Wang Lei
Background The remodeling of extracellular matrix often fails chemotherapeutic agents to fight intrahepatic cholangiocarcinoma (ICC). The cGAS/STING pathway can trigger the innate immune response to obtain better immunotherapeutic outcomes. Results A cLipG/CuET nanocomposite was designed and synthesized based on glycyrrhizic acid (GA) and copper diethyldithiocarbamate (CuET). GA can open mitochondrial permeability transition pores (MPTPs), allowing Cu (II) to interrupt mitochondrial function through copper toxicity. By activating the cGAS-STING signaling pathway in macrophages, this mitochondrial-targeting polymer (cLipG/CuET) significantly boosted the production of mitochondrial reactive oxygen species (mtROS), and promoted the escape of damaged mitochondrial DNA (mtDNA) from ICC cells. Consequently, M1 polarization of cancer-associated macrophages enhanced the immune response against ICC. In the mouse model, the intravenous administration of cLipG/CuET transformed the ICC from “cold” into “hot”. Conclusions With a high biosafety, cLipG/CuET exerted a synergistic effect on the immune checkpoint inhibitor αCTLA-4 against ICC, and their combination provided a new therapeutic strategy. Graphical abstract
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BIOMATERIALS
·
2024
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IF 12.8
Yujun Zhang,Shijing Wang,Hyeonji Rha,Chang Xu,Yue Pei,Xiaoyuan Ji,Junmin Zhang,Ruitao Lu,Shaochong Zhang,Zhongjian Xie,Jong Seung Kim
Cancer immunotherapy has been developed to improve therapeutic effects for patients by activating the innate immune stimulator of interferon gene (STING) pathway. However, most patients cannot benefit from this therapy, mainly due to the problems of excessively low immune responses and lack of tumor specificity. Herein, we report a solution to these two problems by developing a bifunctional platform of black phosphorus quantum dots (BPQDs) for STING agonists. Specifically, BPQDs could connect targeted functional groups and regulate surface zeta potential by coordinating metal ions to increase loading (over 5 times) while maintaining high universality (7 STING agonists). The controlled release of STING agonists enabled specific interactions with their proteins, activating the STING pathway and stimulating the secretion release of immunosuppressive factors by phosphorylating TBK1 and IFN-IRF3 and secreting high levels of immunostimulatory cytokines, including IL-6, IFN-α, and IFN-β. Moreover, the immunotherapy was enhanced was enhanced mild photothermal therapy (PTT) of BPQDs platform, producing enough T cells to eliminate tumors and prevent tumor recurrence . This work facilitates further research on targeted delivery of small-molecule immune drugs to enhance the development of clinical immunotherapy.
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Journal of Advanced Research
·
2026
·
IF 17.1
Guifang Fan,Xin Li,Yiran Li,Shuni Duan,Wenqing Qin,Yajing Li,Rong Sun,Kaihong Xie,Zixuan Huo,Jiaorong Qu,Runping Liu
Introduction Cholestatic liver disease can progress to advanced stages if left untreated and is lack of effective therapeutic options, highlighting the urgent need for new therapeutic targets. Objectives We aim to investigate the involvement of conjugated bile acids and STING signaling in the progression of cholestatic liver diseases. Methods We studied cholestatic liver injury in patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), as well as in Abcb4 -/- mice and in mice subjected to bile duct ligation (BDL). Single-cell RNA sequencing (scRNA-seq) of clinical samples, bulk RNA sequencing (RNA-seq) of isolated primary hepatic cells, and abundant biochemical analysis were analyzed to reveal the damage-response pattern during cholestasis. Results We found that STING activation was correlated with the severity of liver injuries in patients with PBC and PSC, as well as in BDL and Abcb4 -/- mice. Tmem173 -/- mice exhibited significant protection against cholestasis-induced ductular reaction, inflammation, and fibrosis. Mechanistically, our results uncovered the cellular heterogeneity of the damage-response pattern during cholestasis. In cholangiocytes, substantial accumulation of conjugated primary bile acids significantly induced mitochondrial damage through the opening of the mitochondrial permeability transition pore, resulting in the production and leakage of oxidized DNA, which facilitates the establishment of senescence-associated secretory phenotype (SASP) by activating STING. The chemoattractive SASP of cholangiocytes then promoted the infiltration and activation of macrophages. Additionally, damage-associated molecular patterns derived from cholangiocytes further triggered the activation of inflammasome and non-lethal pyroptosis in macrophages, which were abrogated by pharmacological or genetic blockade of STING. Conclusion The present study delineates a novel intrahepatic damage-response map during cholestasis and underscores STING signaling as a promising therapeutic target for cholangiopathies.
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BIOSCIENCE REPORTS
·
2026
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IF 4.5
Ma Runtao,Song Yue,Zhang Lijun,Wang Peng,Chen Jiaqi,Chen Tianqi,Zhu Guangyao,Pan Qingrong,Ma Mengyu,Mo Qigui,Lu Surui,Yu Xuanjie,Guo Yi
Diabetic kidney disease (DKD) is a common microvascular complication of diabetes and is closely linked to chronic inflammation. This study examined how the β-adrenergic receptor agonist isoprenaline (ISO) protected against DKD by regulating the cGAS–STING signaling pathway through multiple targets. In a streptozotocin-induced diabetic mouse model, ISO treatment improved glomerulosclerosis, reduced podocyte injury and proteinuria, and suppressed renal inflammation. Network pharmacology and molecular docking suggested that, besides activating ADRB1/2, ISO may interact with AKT1, SRC, GSK3β, and EGFR, which are involved in cGAS–STING signalling regulation. These findings indicate that ISO alleviates DKD by inhibiting excessive activation of the cGAS–STING pathway through multi-target coordination, providing a new perspective for therapeutic development.
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Acta Biomaterialia
·
2024
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IF 9.4
Peng Wang,Yinfeng Wang,Huimin Li,Miaomiao Wang,Yue Wang,Xiaofei Wang,Lang Ran,Huan Xin,Jingyi Ma,Geng Tian,Wenjuan Gao,Guilong Zhang
Herein, we developed a doxorubicin (Dox)-loaded and 4T1 cancer cell membrane-modified hydrogenated manganese oxide nanoparticles (mHMnO-Dox) to elicit systemic antitumor immune responses. The results revealed that mHMnO-Dox actively recognized tumor cells and then effectively delivered Dox into the cells. Upon entering tumor cells, the mHMnO-Dox underwent rapid degradation and abundant release of Mn 2+ and chemotherapeutic drugs. The released Mn 2+ not only catalysed a Fenton-type reaction to produce excessive reactive oxygen species (ROS) but also activated the cGAS-STING pathway to boost dendritic cell (DC) maturation. This process increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. In addition, the released Dox could contribute to a chemotherapeutic effect, while activating DC cells and subsequently intensifying immune responses through immunogenic cell death (ICD) of tumor cells. Consequently, the mHMnO-Dox suppressed the primary and distal tumor growth and inhibited tumor relapse and metastasis, as well as prolonged the lifespan of tumor-bearing mice. Thus, the mHMnO-Dox multimodally activated DC cells to demonstrate synergistic antitumor activity, which was mediated via the activation of the cGAS-STING signalling pathway to regulate tumor microenvironment, ICD-mediated immunotherapy and ROS-mediated CDT. These findings suggest the therapeutic potential of mHMnO-Dox in cancer immunotherapy. Statement of significance A cancer cell membrane-camouflaged hydrogenated mesoporous manganese oxide (mHMnO) has been developed as a cGAS-STING agonist and ICD inducer. The mHMnO effectively induced abundance of ROS production in cancer cells, which caused cancer cell death and then promoted DC maturation via tumour-associated antigen presentation. Meanwhile, the mHMnO significantly activated cGAS-STING pathway to facilitate DC maturation and cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment, which further enhanced tumour immune response. In addition, the combination of the mHMnO and Dox could synergistically promote tumour ICD and then multimodally induce DC maturation, achieving an enhanced CIT. Overall, this study provides a potential strategy to design novel immunologic adjuvant for enhanced CIT.
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Cell Death Discovery
·
2023
·Vol. 9
·期 1
·1-15
·
IF 7
Li Hong-Ying,Wei Ting-Ting,Zhuang Miao,Tan Cheng-Ye,Xie Tian-Hua,Cai Jiping,Yao Yong,Zhu Lingpeng
Cellular senescence is a hallmark of aging and has been linked to age-related diseases. Age-related macular degeneration (AMD), the most common aging-related retinal disease, is prospectively associated with retinal pigment epithelial (RPE) senescence. However, the mechanism of RPE cell senescence remains unknown. In this study, tert-butyl hydroperoxide (TBH)-induced ARPE-19 cells and D-galactose-treated C57 mice were used to examine the cause of elevated iron in RPE cell senescence. Ferric ammonium citrate (FAC)-treated ARPE-19 cells and C57 mice were used to elucidated the mechanism of iron overload-induced RPE cell senescence. Molecular biology techniques for the assessment of iron metabolism, cellular senescence, autophagy, and mitochondrial function in vivo and in vitro. We found that iron level was increased during the senescence process. Ferritin, a major iron storage protein, is negatively correlated with intracellular iron levels and cell senescence. NCOA4, a cargo receptor for ferritinophagy, mediates degradation of ferritin and contributes to iron accumulation. Besides, we found that iron overload leads to mitochondrial dysfunction. As a result, mitochondrial DNA (mtDNA) is released from damaged mitochondria to cytoplasm. Cytoplasm mtDNA activates the cGAS-STING pathway and promotes inflammatory senescence-associated secretory phenotype (SASP) and cell senescence. Meanwhile, iron chelator Deferoxamine (DFO) significantly rescues RPE senescence and retinopathy induced by FAC or D-gal in mice. Taken together, these findings imply that iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Inhibiting iron accumulation may represent a promising therapeutic approach for age-related diseases such as AMD.
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