Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway
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Le résumé fourni par la source
Abstract Background Cervical cancer (CC) remains a significant global health challenge for women, especially in advanced stages where effective treatments are limited. Current immunotherapies, including PD-1/PD-L1 blockades and adoptive T cell therapies, show limited response rates and durability. Dimethyl fumarate (DMF), an FDA-approved drug for autoimmune diseases, has demonstrated direct antitumor activity in several cancers. However, its influence on anti-tumor immunity and its function in CC remain poorly understood. This study aims to investigate the therapeutic potential of DMF in CC models and elucidate its underlying mechanisms of action. Methods CC cell lines and mouse models were treated with DMF. Transcriptomics profiling of cervical cancer cells following DMF treatment were analyzed by RNA-seq and bioinformatic methods. Mitochondrial DNA (mtDNA) release, and cGAS-STING activation were assessed via qPCR, immunofluorescence, immunoblotting and ELISA. CD8 + T cell recruitment was analyzed by flow cytometry. Combinatorial therapies (DMF + anti-PD-1/TILs) were tested in syngeneic or patient-derived xenografts (PDX) models. Results DMF treatment induces mitochondrial dysfunction in tumor cells, resulting in the release of mtDNA into the cytosol. The cytosolic mtDNA in turn activates the cGAS-STING-TBK1 pathway and type I interferon response, leading to the secretion of CCL5 and CXCL10, thereby enhancing CD8⁺ T cell infiltration. Additionally, DMF exhibits synergistic effect with PD-1 blockade in murine CC model, and can enhance the therapeutic efficacy of adoptively transferred T cells toward CC in patient-derived xenografts model. Conclusion This work elucidated that DMF reprograms CC cells to activate the mtDNA-cGAS-STING pathway, fostering a chemokine-rich microenvironment that recruits CD8 + T cells. The synergistic effect of DMF and PD-1 blockade or TIL therapy underscores its potential as an immunostimulatory adjuvant. These findings suggest that DMF holds promise as a novel immunotherapeutic strategy for improving clinical outcomes in CC. Graphical Abstract
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Dimethyl fumarate reprograms cervical cancer cells to enhance antitumor immunity by activating mtDNA-cGAS-STING pathway
- Date Crossref
- 20/10/2025
- Éditeur
- Springer Science and Business Media LLC
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Huazhong University of Science and Technology State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases pays non établi dans la noticeUniversité ou école supérieure
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School of Medicine Women's Hospital pays non établi dans la noticeÉtablissement de santé
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Tongji Hospital pays non établi dans la noticeÉtablissement de santé
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Zhejiang Provincial People's Hospital pays non établi dans la noticeÉtablissement de santé
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Hangzhou Medical College Department of Medical Oncology pays non établi dans la noticeUniversité ou école supérieure
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Union Hospital pays non établi dans la noticeÉtablissement de santé
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Wuhan Union Hospital pays non établi dans la noticeÉtablissement de santé
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Ministry of Education of the People's Republic of China pays non établi dans la noticeOrganisme public
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Chinese Academy of Medical Sciences & Peking Union Medical College pays non établi dans la noticeUniversité ou école supérieure
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Saudi Center for Organ Transplantation pays non établi dans la noticeOrganisme public
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School of Basic Medicine Department of Pathogen Biology pays non établi dans la noticeUniversité ou école supérieure
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Tongji Medical College Department of Obstetrics and Gynecology pays non établi dans la noticeUniversité ou école supérieure
State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases — Huazhong University of Science and Technology, Women's Hospital — School of Medicine et Tongji Hospital, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.