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Here, we identified an association between reduced P53 function and increased expression of the epigenetic regulator TET1 in GBM models. In TP53mut GBM cells, TET1 knockdown influenced genome fragility, including DNA damage, senescence, and telomere shortening. Specifically, our findings are consistent with a model in which TET1 binds to the ROS1 promoter and may help maintain ROS1 expression, likely by keeping the promoter in a hypomethylated state, along with downstream ERK phosphorylation. Conversely, inhibiting TET1 correlates with reduced ROS1 expression, attenuation of ERK signaling, and increased genome fragility. Furthermore, TET1 depletion in tumor cells was associated with altered tumor\u2010associated macrophages biology both in vitro and in vivo, including increased infiltration, differentiation, M1\u2010like polarization, and phagocytic capacity. Notably, combining the TET1 inhibitor Bobcat339 with cisplatin synergistically inhibited TP53mut GBM growth in vitro and in vivo, improving survival without significant toxicity. Our findings suggest that TET1 may serve as a potential mediator of therapy resistance and a promising therapeutic target in TP53mut GBM.<\/jats:p>","DOI":"10.1002\/advs.76517","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T22:23:58Z","timestamp":1783808638000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["TET1 Inhibition Promotes Therapeutic Sensitivity in TP53\u2010Mutant GBM by Influencing Genome Fragility and Altering TAMs Biology"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhuonan","family":"Pu","sequence":"first","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinqiu","family":"Liu","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxuan","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyu","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6738-1122","authenticated-orcid":false,"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingxu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Guo","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingdan","family":"Chen","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tai","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0009-7370","authenticated-orcid":false,"given":"Zhengping","family":"Zhuang","sequence":"additional","affiliation":[{"name":"Neuro\u2010Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health  Bethesda MD USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Feng","sequence":"additional","affiliation":[{"name":"Beijing Neurosurgical Institute Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21613"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07385"},{"key":"e_1_2_12_4_1","doi-asserted-by":"crossref","unstructured":"R.Schulz\u2010Heddergott N.Stark S. 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