A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer
Abstract Background The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome tr...
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BMC
2025-05-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06576-2 |
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| author | Ying Chen Qiaoming Li Zixiang Wang Ling V. Sun Steven X. Hou |
| author_facet | Ying Chen Qiaoming Li Zixiang Wang Ling V. Sun Steven X. Hou |
| author_sort | Ying Chen |
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| description | Abstract Background The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance. Methods We conducted an in vivo chemical screen to identify F1929-1458, which is capable of eliciting an organism-wide response to destroy stem cell tumors in Drosophila. We then performed functional validation using a mouse colorectal cancer graft tumor model established with the CT26 cell line characterized by its high content of CSCs. Single-cell sequencing was employed to analyze alterations in the TME. Small molecule pull-down mass spectrometry, cellular thermal shift assay, drug affinity experiment, and molecular docking were utilized to identify the target of F1929-1458. An in vitro co-culture system was applied to establish that the damage-associated molecular patterns (DAMPs) released by the tumor cells are accountable for the activation of dendritic cells (DCs). Results We demonstrated that F1929-1458 treatment enhanced T cell infiltration and T cell mediated tumor regression, its anti-tumor effect was nullified in nude mice and was abolished after anti-CD3 neutralizing antibody treatment. We found that F1929-1458 binds NFKB1 to activate the NF-κB signaling pathway in tumor cells. The activation further elicits cellular stress, causing tumor cells to release DAMPs (HMGB1-gDNA complex, ATP, and OxLDL). These DAMPs, in turn, stimulate the cGAS-STING and NLRP3 inflammasome pathways in DCs, resulting in the generation of type I IFNs and IL-1β. These cytokines facilitate the maturation of DCs and antigen presentation, ultimately enhancing T cell-mediated anti-tumor immunity. Additionally, we showed that the combination of F1929-1458 and the anti-PD-1 antibody exhibited a synergistic anti-tumor effect. Conclusion Our study identified a novel NFKB1 agonist that promotes anti-tumor immunity by remodeling the TME and activating DCs and that may provide a new way to overcome resistance to current anti-tumor immunotherapy in colorectal cancer. |
| format | Article |
| id | doaj-art-b859ace6fc704ca4afd51191bea4a992 |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | BMC |
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| series | Journal of Translational Medicine |
| spelling | doaj-art-b859ace6fc704ca4afd51191bea4a9922025-08-20T03:48:18ZengBMCJournal of Translational Medicine1479-58762025-05-0123111910.1186/s12967-025-06576-2A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancerYing Chen0Qiaoming Li1Zixiang Wang2Ling V. Sun3Steven X. Hou4Department of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children’s Hospital, Zhongshan Hospital, Fudan UniversityDepartment of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children’s Hospital, Zhongshan Hospital, Fudan UniversityDepartment of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children’s Hospital, Zhongshan Hospital, Fudan UniversityDepartment of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children’s Hospital, Zhongshan Hospital, Fudan UniversityDepartment of Cell and Developmental Biology at School of Life Sciences, State Key Laboratory of Genetic Engineering, Institute of Metabolism and Integrative Biology, Human Phenome Institute, Children’s Hospital, Zhongshan Hospital, Fudan UniversityAbstract Background The immunosuppressive nature of the tumor microenvironment (TME) and the existence of cancer stem cells (CSCs) present significant hurdles in tumor therapy. The identification of therapeutic agents that can target both CSCs and the TME could be a potential approach to overcome treatment resistance. Methods We conducted an in vivo chemical screen to identify F1929-1458, which is capable of eliciting an organism-wide response to destroy stem cell tumors in Drosophila. We then performed functional validation using a mouse colorectal cancer graft tumor model established with the CT26 cell line characterized by its high content of CSCs. Single-cell sequencing was employed to analyze alterations in the TME. Small molecule pull-down mass spectrometry, cellular thermal shift assay, drug affinity experiment, and molecular docking were utilized to identify the target of F1929-1458. An in vitro co-culture system was applied to establish that the damage-associated molecular patterns (DAMPs) released by the tumor cells are accountable for the activation of dendritic cells (DCs). Results We demonstrated that F1929-1458 treatment enhanced T cell infiltration and T cell mediated tumor regression, its anti-tumor effect was nullified in nude mice and was abolished after anti-CD3 neutralizing antibody treatment. We found that F1929-1458 binds NFKB1 to activate the NF-κB signaling pathway in tumor cells. The activation further elicits cellular stress, causing tumor cells to release DAMPs (HMGB1-gDNA complex, ATP, and OxLDL). These DAMPs, in turn, stimulate the cGAS-STING and NLRP3 inflammasome pathways in DCs, resulting in the generation of type I IFNs and IL-1β. These cytokines facilitate the maturation of DCs and antigen presentation, ultimately enhancing T cell-mediated anti-tumor immunity. Additionally, we showed that the combination of F1929-1458 and the anti-PD-1 antibody exhibited a synergistic anti-tumor effect. Conclusion Our study identified a novel NFKB1 agonist that promotes anti-tumor immunity by remodeling the TME and activating DCs and that may provide a new way to overcome resistance to current anti-tumor immunotherapy in colorectal cancer.https://doi.org/10.1186/s12967-025-06576-2F1929-1458NFKB1NF-κB signaling pathwayDAMPsAnti-tumor immunity |
| spellingShingle | Ying Chen Qiaoming Li Zixiang Wang Ling V. Sun Steven X. Hou A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer Journal of Translational Medicine F1929-1458 NFKB1 NF-κB signaling pathway DAMPs Anti-tumor immunity |
| title | A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer |
| title_full | A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer |
| title_fullStr | A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer |
| title_full_unstemmed | A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer |
| title_short | A novel NFKB1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti-tumor immunity in colorectal cancer |
| title_sort | novel nfkb1 agonist remodels tumor microenvironment and activates dendritic cells to promote anti tumor immunity in colorectal cancer |
| topic | F1929-1458 NFKB1 NF-κB signaling pathway DAMPs Anti-tumor immunity |
| url | https://doi.org/10.1186/s12967-025-06576-2 |
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