Zhang Liyang, Yang Jingxuan, Zhou Zhijun, Ren Yu, Chen Bo, Tang Anliu, Zhang Kailiang, Li Chuntao, Zhou Hongshu, Fung Kar-Ming, Xu Chao, Kang Chunsheng, Battiste James D, Bronze Michael S, Houchen Courtney W, Liu Zhixiong, Dunn Ian F, Cavenee Webster K, Li Min
Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
Proc Natl Acad Sci U S A. 2025 May 6;122(18):e2427073122. doi: 10.1073/pnas.2427073122. Epub 2025 Apr 30.
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.
胶质母细胞瘤（GBM）是最具侵袭性的脑癌形式，治疗选择有限。虽然小胶质细胞促进GBM进展，但其促进促肿瘤免疫环境的机制仍知之甚少。我们确定锌转运蛋白Zrt和Irt样蛋白4（ZIP4）是GBM免疫格局的关键调节因子。在原位小鼠模型中，ZIP4驱动肿瘤生长和行为改变。从机制上讲，ZIP4通过携带髓系细胞表达的触发受体1（TREM1）的肿瘤衍生细胞外囊泡调节小胶质细胞可塑性，这一过程由GBM细胞中锌依赖性转录因子锌指E盒结合同源框1调控。TREM1通过脾酪氨酸激酶-丙酮酸脱氢酶激酶-信号转导和转录激活因子3（SYK-PDK-STAT3）信号轴增强小胶质细胞可塑性，最终促进有利于肿瘤进展的免疫环境。ZIP4缺失或TREM1抑制通过破坏肿瘤-小胶质细胞相互作用减弱体内肿瘤生长和行为效应。这些发现确立了ZIP4作为GBM免疫格局的关键调节因子，并提示了一个有前景的治疗靶点以对抗小胶质细胞介导的肿瘤进展。
