Author: Luo, Ren ; Yao, Zhuoran ; Xue, Jianxin ; Kang, Kai ; Lin, Guo ; Lu, You ; Peng, Zichong ; Liu, Shanghai ; Zheng, Yue ; Yi, Linglu ; Tong, Ruizhan ; Zhou, Pengfei ; Liao, Shuangsi ; Wang, Hui

PURPOSEThe effectiveness of immune checkpoint inhibitors in solid tumors is limited and heavily dependent on the tumor microenvironment (TME). Radiotherapy (RT) reshapes the TME, promoting T-cell infiltration. We explored the combined anti-tumor effects of the stimulator of interferon genes (STING) agonist with low-dose RT and immunotherapy.METHODS AND MATERIALSTumor cell lines (PRM-SCLC, MC38, and LL2) were treated with the STING agonist diABZI (0.001-10 µM) to assess cytotoxicity. The mRNA expression levels of chemokines and cytokines in tumor cells were quantitatively analyzed in conjunction with RT to assess immune activation. Flow cytometry assessed bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) maturation. Subcutaneous tumor-bearing mouse models (PRM-SCLC, MC38, LL2) were used to monitor tumor volume, body weight, and survival. Tumor samples were collected for flow cytometry, immunofluorescence, immunohistochemistry, and transcriptome sequencing. Bilateral tumor models assessed the abscopal effect, with tumor and tumor-draining lymph node (TDLN) samples collected.RESULTSThe STING agonist diABZI did not directly inhibit tumor cell proliferation at tested concentrations. However, when combined with RT, diABZI significantly upregulated chemokines and IFN-β mRNA levels in tumor cells, while mitigating the RT-induced rise in TGF-β levels. In vitro, BMDCs and BMDMs treated with STING agonist + RT showed increased maturation. In tumor-bearing mice, STING agonist enhanced the efficacy of RT, chemotherapy, and immunotherapy. Adding STING agonist to LDRT + αPD-1 activated tumor-infiltrating CD45⁺, CD8⁺, CD4⁺ T cells, NK cells, and dendritic cells, and promoted M1 macrophage polarization. Transcriptome analysis showed enhanced antigen presentation and T cell activation. In bilateral tumor models, triple therapy reduced both primary and distant tumor volumes, with increased T cell infiltration and a higher presence of TCF1⁺ PD-1⁺ T_SL cells in TDLNs.CONCLUSIONSSTING agonist boosts immune activation and cell recruitment in the TME, enhancing immunotherapy response. It also amplifies the abscopal effect of RT, promoting systemic anti-tumor immunity with clinical translational potential.

18 Mar 2025·ACS Nano

Boosting Peroxidase-Mimetic Activity of FeMn-NC_e Dual-Atom Radiosensitizing Nanozymes for Augmented Radiodynamic Immunotherapy

Article

Author: Mu, Min ; Zou, Bingwen ; Chen, Bo ; Wang, Yinggang ; Fan, Rangrang ; Guo, Gang ; Xiao, Susu ; Li, Hui ; Feng, Chenqian

Dual-atom nanozymes (DAzymes) have garnered considerable attention as catalysts for reactive oxygen species (ROS)-based therapies, effectively leveraging ROS generation within the tumor microenvironment (TME). Herein, we introduce the FeMn-NC_e DAzymes, which are meticulously engineered for enhanced peroxidase (POD)-mimetic activity and potent radiosensitization to advance radioimmunotherapy. Density functional theory (DFT) calculations reveal that FeMn-NC_e DAzymes lower the energy barrier and increase the substrate affinity, enabling highly efficient catalytic performance. Within the TME, these DAzymes efficiently convert overexpressed hydrogen peroxide (H₂O₂) into hydroxyl radicals (^•OH), potentially activating the cGAS-STING immune pathway. This POD-mimetic catalysis is further accelerated under X-ray irradiation, significantly enhancing radiosensitization. Additionally, a uniform coating of ultrasmall gold nanoparticles on FeMn-NC_e significantly enhances X-ray absorption within cancer cells. The incorporation of the STING agonist diABZI onto the DAzymes induces long-term antitumor immunity, reprograms the immunosuppressive TME, and effectively suppresses tumor growth and metastasis following a single low-dose X-ray treatment. This work highlights a valuable strategy for designing DAzymes to advance radiodynamic immunotherapy.

01 Mar 2025·Allergy

STING‐dependent induction of neutrophilic asthma exacerbation in response to house dust mite

Article

Author: Boussad, Rania ; Quesniaux, Valerie F. ; Radzikowska, Urszula ; Savigny, Florence ; Sokolowska, Milena ; Edwards, Michael R. ; Togbe, Dieudonnée ; Rose, Stéphanie ; Culerier, Elodie ; da Silva, Gabriel V. L. ; Veront, Chloé ; Jackson, David J. ; Johnston, Sebastian L. ; Malissen, Bernard ; Maillet, Isabelle ; Ryffel, Bernhard ; Messaoud‐Nacer, Yasmine

AbstractBackgroundSevere refractory, neutrophilic asthma remains an unsolved clinical problem. STING agonists induce a neutrophilic response in the airways, suggesting that STING activation may contribute to the triggering of neutrophilic exacerbations. We aim to determine whether STING‐induced neutrophilic lung inflammation mimics severe asthma.MethodsWe developed new models of neutrophilic lung inflammation induced by house dust mite (HDM) plus STING agonists diamidobenzimidazole (diABZI) or cGAMP in wild‐type, and conditional‐STING‐deficient mice. We measured DNA damage, cell death, NETs, cGAS/STING pathway activation by immunoblots, N1/N2 balance by flow cytometry, lung function by plethysmography, and Th1/Th2 cytokines by multiplex. We evaluated diABZI effects on human airway epithelial cells from healthy or patients with asthma, and validated the results by transcriptomic analyses of rhinovirus infected healthy controls vs patients with asthma.ResultsDiABZI administration during HDM challenge increased airway hyperresponsiveness, neutrophil recruitment with prominent NOS2+ARG1− type 1 neutrophils, protein extravasation, cell death by PANoptosis, NETs formation, extracellular dsDNA release, DNA sensors activation, IFNγ, IL‐6 and CXCL10 release. Functionally, STING agonists exacerbated airway hyperresponsiveness. DiABZI caused DNA and epithelial barrier damage, STING pathway activation in human airway epithelial cells exposed to HDM, in line with DNA‐sensing and PANoptosis pathways upregulation and tight‐junction downregulation induced by rhinovirus challenge in patients with asthma.ConclusionsOur study identifies that triggering STING in the context of asthma induces cell death by PANoptosis, fueling the flame of inflammation through a mixed Th1/Th2 immune response recapitulating the features of severe asthma with a prognostic signature of type 1 neutrophils.

100 Deals associated with Dimeric Amidobenzimidazole

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Indication	Highest Phase	Country/Location	Organization	Date
Osteoporosis	Preclinical	China	Peking Union Medical College	14 Jun 2024
Neoplasms	Discovery	United States	Mersana Therapeutics, Inc.	24 Jul 2023

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