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CRISPRa-identified transcription factors reprogram glioblastoma into dendritic cell-like cells to elicit systemic antitumor immunity.

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Τίτλος: CRISPRa-identified transcription factors reprogram glioblastoma into dendritic cell-like cells to elicit systemic antitumor immunity.
Συγγραφείς: Liu X; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China., Zhu M; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Zou C; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Cao Z; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Wang Y; Air Force Medical Center of PLA, Air Force Medical University, Beijing 100000, China., Yang G; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China., Liu X; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Wu Y; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Yu D; Department of Neurosurgery, General Hospital of Central Theater Command, Wuhan, China., Zheng D; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Zhang K; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Li J; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China., Zhang W; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Wang S; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Qin H; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China., Hao Q; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Zhang Y; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Yin A; Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China., He Y; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China., He L; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China., Luo X; School of Basic Medicine, Fourth Military Medical University, Xi'an, China. Electronic address: 631912271@qq.com., Lin W; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China; Department of Aviation Medicine, Xijing Hospital, Xi'an, China. Electronic address: linwei@fmmu.edu.cn., Li M; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China. Electronic address: limeng@fmmu.edu.cn., Gu J; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China. Electronic address: gujintao@fmmu.edu.cn.
Πηγή: Cell reports. Medicine [Cell Rep Med] 2026 Sep 15; Vol. 7 (9), pp. 103018. Date of Electronic Publication: 2026 Sep 01.
Τύπος έκδοσης: Journal Article
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Cell Press Country of Publication: United States NLM ID: 101766894 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2666-3791 (Electronic) Linking ISSN: 26663791 NLM ISO Abbreviation: Cell Rep Med Subsets: MEDLINE
Imprint Name(s): Original Publication: [Cambridge, MA] : Cell Press, [2020]-
Ιατρικοί όροι (MeSH): Glioblastoma*/immunology , Glioblastoma*/genetics , Glioblastoma*/pathology , Glioblastoma*/therapy , Dendritic Cells*/immunology , Dendritic Cells*/metabolism , Transcription Factors*/metabolism , Transcription Factors*/genetics , Cellular Reprogramming*/genetics , Brain Neoplasms*/immunology , Brain Neoplasms*/pathology , Brain Neoplasms*/genetics, Tumor Microenvironment/immunology ; Immunotherapy/methods ; Animals ; Humans ; Mice ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic
Περίληψη: Although immunotherapy has transformed the treatment landscape for many types of cancer, its therapeutic efficacy in glioblastoma (GBM) is limited by insufficient antigen presentation and the immunogenic cell exclusion in the tumor microenvironment. Here, we develop a candidate-based CRISPR activation (CRISPRa) functional screen to identify regulators of conventional dendritic cell (cDC)-fate specification. We determine that the transcription factors Zfp366/Znf366, Pu.1, Irf8, and Batf3 (ZPIB) are sufficient to convert GBM cells into cDC-like cells. ZPIB-mediated reprogramming results in global transcriptional and epigenetic remodeling in glioma cells. Single-cell RNA sequencing (scRNA-seq) profiling also reveals efficient and dynamic reprogramming of GBM cells to cDCs in vivo. Moreover, reprogrammed tumor cells remodel the microenvironment and elicit systemic tumor-eradicating and durable antitumor immunity in multiple mouse GBM models. Antitumor immunity elicited by ZPIB-DCs is synergistic with immune checkpoint inhibitors. Finally, we evaluate the clinical applicability of this approach by generating ZPIB-DCs from GBM patients within a humanized model. Our study represents a cellular reprogramming therapeutic strategy with broad implications for clinical immunotherapy.
(Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.)
Competing Interests: Declaration of interests The authors declare no competing interests.
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Contributed Indexing: Keywords: CRISPR screen; cancer immunotherapy; glioblastoma; lineage reprogramming; tumor microenvironment
Substance Nomenclature: 0 (Transcription Factors)
Entry Date(s): Date Created: 20260901 Date Completed: 20260915 Latest Revision: 20260922
Update Code: 20260922
PubMed Central ID: PMC13589486
DOI: 10.1016/j.xcrm.2026.103018
PMID: 42679804
Βάση Δεδομένων: MEDLINE
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  Data: CRISPRa-identified transcription factors reprogram glioblastoma into dendritic cell-like cells to elicit systemic antitumor immunity.
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  Data: <searchLink fieldCode="AU" term="%22Liu+X%22">Liu X</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Zhu+M%22">Zhu M</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Zou+C%22">Zou C</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Cao+Z%22">Cao Z</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Wang+Y%22">Wang Y</searchLink>; Air Force Medical Center of PLA, Air Force Medical University, Beijing 100000, China.<br /><searchLink fieldCode="AU" term="%22Yang+G%22">Yang G</searchLink>; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Liu+X%22">Liu X</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Wu+Y%22">Wu Y</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Yu+D%22">Yu D</searchLink>; Department of Neurosurgery, General Hospital of Central Theater Command, Wuhan, China.<br /><searchLink fieldCode="AU" term="%22Zheng+D%22">Zheng D</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Zhang+K%22">Zhang K</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Li+J%22">Li J</searchLink>; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Zhang+W%22">Zhang W</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Wang+S%22">Wang S</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Qin+H%22">Qin H</searchLink>; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Hao+Q%22">Hao Q</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Zhang+Y%22">Zhang Y</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Yin+A%22">Yin A</searchLink>; Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.<br /><searchLink fieldCode="AU" term="%22He+Y%22">He Y</searchLink>; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22He+L%22">He L</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China.<br /><searchLink fieldCode="AU" term="%22Luo+X%22">Luo X</searchLink>; School of Basic Medicine, Fourth Military Medical University, Xi'an, China. Electronic address: 631912271@qq.com.<br /><searchLink fieldCode="AU" term="%22Lin+W%22">Lin W</searchLink>; Department of Neurosurgery, Xijing Hospital, Xi'an 710000, China; Department of Aviation Medicine, Xijing Hospital, Xi'an, China. Electronic address: linwei@fmmu.edu.cn.<br /><searchLink fieldCode="AU" term="%22Li+M%22">Li M</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China. Electronic address: limeng@fmmu.edu.cn.<br /><searchLink fieldCode="AU" term="%22Gu+J%22">Gu J</searchLink>; State Key Laboratory of Cancer Biology, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710000, China. Electronic address: gujintao@fmmu.edu.cn.
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  Data: <searchLink fieldCode="MM" term="%22Glioblastoma%22">Glioblastoma*</searchLink>/<searchLink fieldCode="MM" term="%22Glioblastoma+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Glioblastoma%22">Glioblastoma*</searchLink>/<searchLink fieldCode="MM" term="%22Glioblastoma+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Glioblastoma%22">Glioblastoma*</searchLink>/<searchLink fieldCode="MM" term="%22Glioblastoma+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Glioblastoma%22">Glioblastoma*</searchLink>/<searchLink fieldCode="MM" term="%22Glioblastoma+therapy%22">therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Dendritic+Cells%22">Dendritic Cells*</searchLink>/<searchLink fieldCode="MM" term="%22Dendritic+Cells+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Dendritic+Cells%22">Dendritic Cells*</searchLink>/<searchLink fieldCode="MM" term="%22Dendritic+Cells+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcription+Factors%22">Transcription Factors*</searchLink>/<searchLink fieldCode="MM" term="%22Transcription+Factors+metabolism%22">metabolism</searchLink> <br /><searchLink fieldCode="MM" term="%22Transcription+Factors%22">Transcription Factors*</searchLink>/<searchLink fieldCode="MM" term="%22Transcription+Factors+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Cellular+Reprogramming%22">Cellular Reprogramming*</searchLink>/<searchLink fieldCode="MM" term="%22Cellular+Reprogramming+genetics%22">genetics</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain+Neoplasms%22">Brain Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Neoplasms+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain+Neoplasms%22">Brain Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Neoplasms+pathology%22">pathology</searchLink> <br /><searchLink fieldCode="MM" term="%22Brain+Neoplasms%22">Brain Neoplasms*</searchLink>/<searchLink fieldCode="MM" term="%22Brain+Neoplasms+genetics%22">genetics</searchLink><br /><searchLink fieldCode="MH" term="%22Tumor+Microenvironment%22">Tumor Microenvironment</searchLink>/<searchLink fieldCode="MH" term="%22Tumor+Microenvironment+immunology%22">immunology</searchLink> ; <searchLink fieldCode="MH" term="%22Immunotherapy%22">Immunotherapy</searchLink>/<searchLink fieldCode="MH" term="%22Immunotherapy+methods%22">methods</searchLink> ; <searchLink fieldCode="MH" term="%22Animals%22">Animals</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Mice%22">Mice</searchLink> ; <searchLink fieldCode="MH" term="%22Cell+Line%2C+Tumor%22">Cell Line, Tumor</searchLink> ; <searchLink fieldCode="MH" term="%22Gene+Expression+Regulation%2C+Neoplastic%22">Gene Expression Regulation, Neoplastic</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Although immunotherapy has transformed the treatment landscape for many types of cancer, its therapeutic efficacy in glioblastoma (GBM) is limited by insufficient antigen presentation and the immunogenic cell exclusion in the tumor microenvironment. Here, we develop a candidate-based CRISPR activation (CRISPRa) functional screen to identify regulators of conventional dendritic cell (cDC)-fate specification. We determine that the transcription factors Zfp366/Znf366, Pu.1, Irf8, and Batf3 (ZPIB) are sufficient to convert GBM cells into cDC-like cells. ZPIB-mediated reprogramming results in global transcriptional and epigenetic remodeling in glioma cells. Single-cell RNA sequencing (scRNA-seq) profiling also reveals efficient and dynamic reprogramming of GBM cells to cDCs in vivo. Moreover, reprogrammed tumor cells remodel the microenvironment and elicit systemic tumor-eradicating and durable antitumor immunity in multiple mouse GBM models. Antitumor immunity elicited by ZPIB-DCs is synergistic with immune checkpoint inhibitors. Finally, we evaluate the clinical applicability of this approach by generating ZPIB-DCs from GBM patients within a humanized model. Our study represents a cellular reprogramming therapeutic strategy with broad implications for clinical immunotherapy.<br /> (Copyright © 2026 The Author(s). Published by Elsevier Inc. All rights reserved.)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Declaration of interests The authors declare no competing interests.
– Name: Ref
  Label: References
  Group: RefInfo
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  Data: <i>Keywords: </i>CRISPR screen; cancer immunotherapy; glioblastoma; lineage reprogramming; tumor microenvironment
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              Text: 2026 Sep 15
              Type: published
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