JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2026
·
IF 14.3
Jia-Rui Du,Mu-Le Tu,Yong-Xu Xia,Yuan-Qiang Lin,Rui Yang,Chang Weng,Yi Liu,Hao Zhang,Hui Wang,Wen-Jie Feng,Deng-Ke Teng
Nanovaccines based on immunogenic cell death (ICD) present a promising strategy in tumor immunotherapy, serving as a bridge connecting tumor cell death to the induction of anti-tumor immunity. However, their efficacy is severely limited by the immunologically silent nature of apoptosis-dependent ICD and the immunosuppressive tumor microenvironment (TME). In this work, we designed a metal‒polyphenol network nanovaccine (SRF@FeShik-cGAMP/HA). Upon reaching the tumor tissue through specific targeting, the nanovaccines disassemble within the tumor cells, releasing the Fenton reaction catalyst ferrous iron (Fe 2+ ), the system Xc- inhibitor sorafenib (SRF), and necroptosis inducer shikonin. Fe 2+ , SRF, and shikonin collectively promote the accumulation of lipid peroxide and amplify ferroptosis by providing an exogenous iron source, inhibiting glutathione biosynthesis, and boosting reactive oxygen species production, respectively. Meanwhile, shikonin induces necroptosis. The combination of ferroptosis and necroptosis overcomes the limitation of tumor immune silencing and triggers a strong ICD. Simultaneously, the immune adjuvant 2'3'-cyclic-GMP-AMP (cGAMP) activates the STING pathway, reversing the immunosuppressive TME and enhancing the anti-tumor immune response mediated by ICD. The synergistic action of ferroptosis, necroptosis, and the STING pathway produces a cascade of antitumor immune responses and establishes long-term immune memory. This nanovaccine demonstrates promising therapeutic effects in primary, orthotopic, and recurrent hepatocellular carcinoma (HCC) models. Collectively, our findings present a cancer immunotherapy strategy that exploits dual ferroptosis and necroptosis induction to trigger ICD, bypassing the limitations of apoptosis-dependent pathways. This strategy coordinates with the STING pathway to achieve potent antitumor immunity, providing a promising paradigm for HCC treatment, and offering a promising and translatable path for clinical development.
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Advanced Science
·
2025
·
IF 14.1
Peili Hou,Hongchao Zhu,Xiaonan Sun,Ni Zhang,Song Wang,Xuexing Zheng,Xiaoyun Wang,Yueyue Feng,Fuzhen Zhang,Xingyu Li,Rui Li,Xiaomeng Wang,Yuanyuan Han,Jun Wang,Chuanhong Wang,Xiaoyang Yao,Hongmei Wang,Hongbin He
Precise regulation of stimulator of interferon genes (STING) expression is critical for maintaining immune homeostasis and preventing autoimmune disorders. In this study, phenazine biosynthesis-like domain-containing protein (PBLD) is identified as a key modulator of the STING-dependent antiviral type I interferon (IFN) response by suppressing coiled-coil domain-containing protein 50 (CCDC50)-mediated selective autophagic degradation of STING. Notably, viral infection downregulates PBLD expression through two distinct mechanisms: transcriptional suppression via reduced transcription factor EB (TFEB) activity, and post-translational degradation through an enhanced membrane-associated RING finger protein 2 (MARCH2)-mediated ubiquitin-proteasome pathway. Together, these mechanisms establish a negative feedback loop that facilitates viral immune evasion. Moreover, Pbld -deficient mice exhibit increased susceptibility to human adenovirus type 4 (HAdV-4) infection compared with their wild-type (WT) littermates. Importantly, Pbld- deficiency in the 2,6,10,14-tetramethylpentadecane (TMPD)-induced lupus mice model attenuates STING expression and diminishes autoimmune phenotypes. Clinically, PBLD expression is elevated in patients with systemic lupus erythematosus and positively correlates with STING-driven type I IFN signaling. Taken together, PBLD plays a dual role in STING-mediated innate immunity against viral infection and autoimmunity, highlighting its potential as a therapeutic target for both antiviral infections and autoimmune diseases.
研究领域:
免疫学
·
分子生物学
·
病毒学
·
自身免疫疾病
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先天免疫
·
细胞信号传导
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MACROMOLECULAR BIOSCIENCE
·
2023
·
IF 4.6
Chunru Wang,Yingjie Xiang,Wenjie Ma,Chuanlong Guo,Xiaochen Wu
Ulcerative colitis is a chronic inflammatory bowel disease with a high recurrence rate. Natural phytochemical compounds are increasingly being considered as preventative and supportive treatments for this condition. However, the poor water solubility and stability of many of these compounds limit their effectiveness in vivo. To address this issue, fisetin (FT), a natural phytochemical with poor solubility, was stabilized using silk sericin (SS) to create a composite (SS/FT). The therapeutic potential of the SS/FT on ulcerative colitis was extensively investigated, and the results showed that it effectively alleviated the body weight loss and colon length shortening induced by dextran sulfate sodium. Notably, SS/FT downregulated the immune response, decreased colonic histopathological lesions, and reduced the cGAS/STING signal activation. This suggests that SS/FT may offer a promising therapy for treating ulcerative colitis. This article is protected by copyright. All rights reserved
研究领域:
药理学
·
炎症性肠病
·
天然产物化学
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TOXICOLOGY AND APPLIED PHARMACOLOGY
·
2025
·
IF 3.4
Yonglong Jin,Nina Dong,Shosei Shimizu,Yinuo Li,Yuan Yao,Hong Qiao,Xiguang Liu,Shuai Liu,Chuanlong Guo,Lijie Wang
The incidence rate and mortality rate of breast cancer remain high, and there is an urgent need for safe and effective drugs. The excellent biological activity of hesperidin (HE) is a potential drug for the treatment of breast cancer. In this study, silk fibroin peptides (SFP) were used as delivery carriers and HE loaded SFP nanofibers (SFP/HE NFs) was prepared. The in vitro results showed that SFP/HE NFs significantly inhibited the proliferation and migration of breast cancer cell MDA-MB-231 compared with free HE. The mechanism results demonstrated that SFP/HE NFs induced apoptosis and DNA double stranded damage (DSBs) and further activated the cyclic monophosphate guanosine adenosine monophosphate synthase- stimulator of interferon gene (cGAS-STING) pathway. The in vivo studies showed that SFP/HE NFs treatment significantly inhibited the growth of breast cancer, with an inhibition rate of 65.9 % (100 mg/kg). In vivo mechanism studies also demonstrated that the anti-tumor activity of SFP/HE NFs was related to the activation of the cGAS-STING pathway. Interestingly, we found that the combination of SFP/HE NFs and cisplatin not only enhanced the anti-tumor activity of cisplatin, but also alleviated cisplatin induced nephrotoxicity. In conclusion, our results demonstrate the benefits of activating the cGAS-STING pathway in the treatment of breast cancer, which is expected to provide potential candidates for combined treatment of breast cancer.
研究领域:
药理学
·
肿瘤学
·
生物材料科学
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LANGMUIR
·
2022
·
IF 4.331
Yurui Xu,Wei Li,Xinyuan Zhou,Ya Gao,Likang Ding,Le Xu,Xianxian Mao,Anwei Zhou,Xiaojian Wang,Xinghai Ning
Although small-molecule agonists of stimulator of interferon genes (STING) show significance in activating the immune system, the dynamic process involved in ligands activating STING remains unclear. Herein, we developed a biochemical strategy, integrating computer simulation and a biochemical engineering approach, to reveal the interaction mechanism between STING and 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an agonist that activates the TANK binding kinase 1-interferon regulatory factor 3 signaling pathway. Specifically, inspired by an analysis of the STING–DMXAA crystal structure, we designed and synthesized DMXAA derivatives to investigate the STING–DMXAA binding model. We identified that the carboxyl moiety of DMXAA was a major pharmacophore responsive to STING activation. In particular, the loss of hydrogen bond interaction between the carboxylic acid of DMXAA and the side chain Thr262 of STING led to STING inhibition. DMXAA N-methyl amide derivative (DNHM) exhibited good inhibitor activity, inhibited STING-mediated interferon production in vitro and in vivo, and effectively attenuated STING-associated inflammatory diseases. Therefore, we provide a new insight into STING–ligand interactions, which may improve the understanding of STING biology.
研究领域:
生物化学
·
分子生物学
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免疫学
·
药理学
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Cell Reports
·
2018
·
IF 8.032
Senlin Li,Ze Hong,Zhe Wang,Fei Li,Jiahao Mei,Lulu Huang,Xiwen Lou,Simeng Zhao,Lihua Song,Wei Chen,Qiang Wang,Heng Liu,Yanni Cai,Huansha Yu,Huimin Xu,Guangzhi Zeng,Quanyi Wang,Juanjuan Zhu,Xing Liu,Ninghua Tan,Chen Wang
Summary cGAS-STING signaling is essential for innate immunity. Its misregulation promotes cancer or autoimmune and autoinflammatory diseases, and it is imperative to identify effective lead compounds that specifically downregulate the pathway. We report here that astin C, a cyclopeptide isolated from the medicinal plant Aster tataricus , inhibits cGAS-STING signaling and the innate inflammatory responses triggered by cytosolic DNAs. Moreover, mice treated with astin C are more susceptible to HSV-1 infection. Consistently, astin C markedly attenuates the autoinflammatory responses in Trex1 −/− BMDM cells and in Trex1 −/− mouse autoimmune disease model. Mechanistically, astin C specifically blocks the recruitment of IRF3 onto the STING signalosome. Collectively, this study characterizes a STING-specific small-molecular inhibitor that may be applied for potentially manipulating the STING-mediated clinical diseases.
研究领域:
免疫学
·
药理学
·
分子生物学
·
传染病学
·
自身免疫学
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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
·
2026
·Vol. 123
·期 11
·e2525897123
·
IF 9.5
Xu He,Lidong Gong,Juqi Zhang,Xiaocong Pang,Yuhui Li,Wei Wei,Yimin Cui,Zhiqiang Lin
Inhibiting stimulator of interferon genes (STING) is critical for treating rheumatoid arthritis (RA), yet achieving precise suppression with high tissue specificity across protein variants remains challenging. Here, we engineer a multilevel, intelligent STING degrader—charge-reversal proteolysis-targeting chimeras (CreTACs)—that efficiently delivers to RA sites and degrades STING variants in humans, mice, and rats. Unlike traditional degraders with systemic toxicity, this charge reversal platform leverages pH-programmed charge inversion: Electroneutrality in circulation (pH 7.4) minimizes toxicity, while acidic-triggered protonation enables a 7.5-fold increase in arthritic joint accumulation (tissue level), pH-gated cellular internalization (80% uptake at pH 6.5 vs. 50% at pH 7.4; cellular level), and enhanced cytoplasmic STING (proton channel) affinity via charge interactions (protein level). In collagen-induced arthritis models, CreTACs outperformed methotrexate by suppressing synovitis and bone erosion without hematological toxicity. This multilevel charge reversal strategy establishes a blueprint for next-generation proteolysis drug-delivery systems or biomaterials, offering transformative potential for healthcare.
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Toxics
·
2026
·Vol. 14
·期 6
·461
·
IF 4.9
Xiangyu Yu,Jiawen Ren,Ying Kang,Shizhi Wang,Jianrui Dou,Yongquan Yu
Glyphosate, the most widely used herbicide worldwide, is now ubiquitous in the environment, posing a growing threat to human health. While accumulating evidence has linked glyphosate exposure to liver injury, the underlying mechanisms remain unclear. In this study, based on data from NHANES 2013–2018, we identified significant associations between glyphosate exposure and abnormal liver function parameters in the general US population. A glyphosate-exposed mouse model was further established, and the results showed that hepatic accumulation of glyphosate induced direct histopathological damage and increased serum AST, ALT, and ALP levels in mice. Combined network toxicology and gene set analyses revealed that glyphosate activated liver macrophages, upregulating genes related to lipid metabolism, inflammation, and pyroptosis. The activation of the pyroptosis pathway was further confirmed by Western blot analysis of NLRP3 inflammasome-associated proteins. Mechanistically, glyphosate disrupted mitochondrial membranes and compromised mitochondrial function, leading to the release of mtDNA, which subsequently activated the cGAS-STING pathway in mouse livers and RAW264.7 macrophages. Moreover, glyphosate-induced NLRP3 activation in RAW264.7 cells was attenuated by the cGAS inhibitor. These findings provide a novel mechanistic insight into glyphosate-induced hepatotoxicity and reinforce the growing concern over its association with liver injury in humans.
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ADVANCED FUNCTIONAL MATERIALS
·
2026
·
IF 19
Jiakun Guo,Jintao Huang,Zuliang Huang,Juan Sun,Yan Wang,Hujing Tan,Di Hu,Chao Deng,Xiaoli Zhu,Zhiyuan Zhong
Activation of stimulator of interferon genes (STING) pathway represents a powerful strategy to generate potent immune responses for cancer immunotherapy, yet clinical translation is hindered by rapid drug clearance, suboptimal activation, and severe local and systemic toxicity. Herein, we report on manganese-coordinated STING-activating microgels (MSM) for safe, sustained, and synergistic activation of anticancer immunity, effectively annihilating various solid tumors. MSM shows efficient encapsulation (>90%) and gradual release of diABZI agonist and Mn 2+ over four weeks, affording cooperative and continuous activation of dendritic cells, MHC upregulation, and proinflammatory cytokine production. Notably, a single intratumoral dose of MSM elicits durable innate and adaptive immunity, remarkably eradicating multiple murine tumors and establishing immune memory against rechallenge. Repurposed as an embolic agent, MSM suppresses orthotopic rabbit VX2 liver tumors and lung metastases through transarterial immunoembolization, demonstrating translational potential across species and tumor models.
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BIOMACROMOLECULES
·
2026
·
IF 5.4
Aolin Sun,Liping Liu,Zichao Huang,Yaxin Zhang,Zhenyi Zhu,Jiangai Long,Ziyue An,Yibo Wang,Yusong Cao,Dianwei Wang,Wantong Song
Macromolecular agonists are promising immunomodulators due to multivalency and tunable architectures. Previously, we showed that branched polyethylenimine (bPEI) conjugated with nitrogen-containing heterocycles activates the STING pathway, with branching being pivotal. Here we ask whether nitrogen is indispensable. We synthesized a library of bPEI conjugates bearing non-nitrogenous ligands (heterocycles, nonheterocycles, and aliphatic chains). While bPEI or ligands alone were inactive, >60% of conjugates induced robust IFN-β secretion across multiple cell types. Representative conjugates promoted STING clustering and TBK1/IRF3 phosphorylation, and genetic ablation of STING or cGAS markedly reduced IFN-β induction. Conjugation mitigated PEI cytotoxicity and minimized NF-κB–driven pro-inflammatory cytokines. Docking, log P analysis, and time-resolved uptake profiling established a physicochemical structure–activity relationship linking ligand rigidity, aromaticity, and hydrophobicity to STING binding, internalization, and IFN-β induction. Thus, nitrogen is not essential; simple hydrophobic modifications suffice within a macromolecular scaffold.
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ACS Applied Materials & Interfaces
·
2026
·
IF 7.8
Xuan Zhang,Yuhao Shi,Songxiang Xie,Zineng Yi,Zijun Jiang,Yiduo Wang,Zhengbao Zha
Conventional adjuvants such as aluminum salts rarely drive robust Th1 immunity, which limits cancer vaccine efficacy. A double-stranded DNA-loaded manganese phosphate nanoadjuvant was generated by dsDNA-templated biomimetic mineralization. The resulting DNA@MnP exhibited favorable physiological stability and pH-responsive release properties: at pH 5.5, the cumulative release rates of Mn2+ and DNA reached 72% and 78%, respectively, within 12 h. Following cytosolic delivery, released Mn2+ from DNA@MnP could augment the cGAS recognition of dsDNA. The cooperative action of Mn2+ and dsDNA produced cascade amplification that potently activated the cGAS-STING pathway in dendritic cells. In vitro experiments demonstrated that DNA@MnP significantly promoted the maturation of BMDCs (with a maturation rate 2.10-fold elevation compared with the control group) and induced RAW264.7 macrophages to polarize toward the M1 phenotype (with an M1/M2 ratio 8.31-fold elevation compared with the control group). Animal experiments demonstrated that DNA@MnP not only significantly enhanced antigen-specific humoral immunity, achieving a 16-fold increase in IgG titers, and elicited a balanced Th1/Th2 response but also effectively activated both innate and adaptive antitumor immunity. Furthermore, this platform was extended to develop a personalized tumor vaccine by encapsulating tumor lysates (TLs) into TLs-loaded manganese phosphate nanovaccines (TLs@MnP). When coadministered with an anti-TIGIT antibody, it potently suppressed tumor growth, recurrence, and metastasis: in the postoperative recurrence model, 42.9% of mice in the TLs@MnP multidose combined with aTIGIT group achieved long-term tumor-free survival. Therefore, this study presented a manganese phosphate-based biomineralization strategy for the concise preparation of autologous tumor vaccines, opening a promising avenue for personalized immunotherapy and clinical translation.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
·
2026
·
IF 6.7
Li Muzi,Zhao Ruyang,Wang Qiqian,Chen Jing,Ma Xiaoyang,Wang Haoran,Li Jinlong
Di(2-ethylhexyl) phthalate (DEHP)
is a widespread environmental
pollutant with neurotoxicity, while lycopene (LYC) is a neuroprotective
dietary carotenoid. This study investigated whether LYC alleviates
DEHP-induced brain injury by regulating microglial activation and
cGAS-STING signaling. ICR mice were treated with LYC (5 mg/kg) and/or
DEHP (500 mg/kg) for 28 days, with results validated in BV2 cells.
In vivo, DEHP exposure impaired spatial learning and memory, triggered
neuronal degeneration, microglial activation and mitochondrial dysfunction,
increased 2 ′ 3 ′ -cGAMP production, and activated cGAS-STING
signaling. LYC supplementation markedly reversed these changes. Network
toxicology, molecular docking, and molecular dynamics suggested cGAS
as a potential LYC target. In vitro, MEHP-induced M1 polarization
was attenuated by LYC, and cGAS silencing verified the pathway’s
critical role in LYC’s protection. These findings indicate
that LYC alleviates DEHP-induced neural damage by maintaining mitochondrial
homeostasis and inhibiting cGAS-STING-mediated microglial activation,
providing a potential nutritional strategy for preventing brain damage
caused by environmental pollutants.
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