A zinc transporter drives glioblastoma progression via extracellular vesicles-reprogrammed microglial plasticity
Glioblastoma (GBM) is the most aggressive form of brain cancer, with limited therapeutic options. While microglia contribute to GBM progression, the mechanisms by which they foster a protumorigenic immune environment remain poorly understood. We identify the zinc transporter Zrt- And Irt-Like Protein 4 (ZIP4) as a pivotal regulator of the GBM immune landscape. In orthotopic mouse models, ZIP4 drives tumor growth and behavioral changes. Mechanistically, ZIP4 modulates microglial plasticity through tumor-derived extracellular vesicles carrying triggering receptor expressed on myeloid cells-1 (TREM1), a process regulated by the zinc-dependent transcription factor Zinc Finger E-box Binding Homeobox 1 in GBM cells. TREM1 enhances microglial plasticity through the spleen associated tyrosine kinase-Pyruvate dehydrogenase kinase-signal transducer and activator of transcription 3 (SYK-PDK-STAT3) signaling axis, ultimately promoting an immune environment favorable to tumor progression. ZIP4 depletion or TREM1 inhibition attenuates tumor growth and behavioral effects in vivo by disrupting the tumor-microglia interaction. These findings establish ZIP4 as a key modulator of the GBM immune landscape and suggest a promising therapeutic target to counteract microglia-mediated tumor progression.
Authors
- Anliu Tang (ORCID: https://orcid.org/0000-0001-9575-7337)
- Jingxuan Yang (ORCID: https://orcid.org/0000-0003-3265-161X)
- Chunsheng Kang (ORCID: https://orcid.org/0000-0002-3255-3369)
- Hongshu Zhou
- Kar‐Ming Fung (ORCID: https://orcid.org/0000-0002-4623-9469)
- Chuntao Li (ORCID: https://orcid.org/0000-0002-1837-0224)
- Zhijun Zhou (ORCID: https://orcid.org/0000-0003-2226-2223)
- James Battiste
- Courtney W. Houchen (ORCID: https://orcid.org/0000-0003-2487-5242)
- Chao Xu (ORCID: https://orcid.org/0000-0002-3821-6187)
- Webster K. Cavenee (ORCID: https://orcid.org/0000-0003-3804-9179)
- Min Li (ORCID: https://orcid.org/0000-0002-3971-9130)
- Liyang Zhang (ORCID: https://orcid.org/0000-0002-4054-1667)
- Bo Chen (ORCID: https://orcid.org/0000-0003-0812-5775)
- Yu Ren (ORCID: https://orcid.org/0000-0002-8582-680X)
- Zhixiong Liu (ORCID: https://orcid.org/0000-0003-3733-7259)
- Kailiang Zhang (ORCID: https://orcid.org/0000-0002-5661-3979)
- Michael S. Bronze (ORCID: https://orcid.org/0000-0002-8770-0872)
- Ian F. Dunn
Institutions
- Central South University (CN)
- Tianjin Medical University General Hospital (CN)
- University of California San Diego (US)
- Third Xiangya Hospital (CN)
- Xiangya Hospital Central South University (CN)
- University of Oklahoma Health Sciences Center (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-04-30
- DOI
- https://doi.org/10.1073/pnas.2427073122
- Citations
- 8
- Primary Topic
- Inflammation biomarkers and pathways
- Type
- article
- Field-Weighted Citation Impact
- 6.38
Funders
- William and Ella Owens Medical Research Foundation
- University of Oklahoma Health Sciences Center