Segura-Collar, BertaCómitre-Mariano, BlancaLópez, Denisse AlcivarModejar-Ruescas, LuciaCaamaño-Moreno, MartaTovar Ambel, ElenaGutiérrez-Martín, JavierGarín, MarinaToldos González, ÓscarHernández Laín, AurelioGargini, RicardoSepúlveda, Juan M.2025-10-212025-10-212025-07-02Segura-Collar B, Cómitre-Mariano B, Alcivar López D, Mondéjar-Ruescas L, Caamaño-Moreno M, Tovar Ambel E, Gutiérrez-Martín J, Garín M, Toldos Ó, Hernández-Laín A, Gargini R, Sepúlveda JM. (2025). The TRIB2–DNMT1 Pathway Generates an Immune-Cold Microenvironment in Glioblastoma, and Its Inhibition Promotes Immunotherapy. Cancer Immunol Res, 13(7):1022–1036. https://doi.org/10.1158/2326-6066.CIR-24-08072326-606610.1158/2326-6066.cir-24-0807https://hdl.handle.net/20.500.14352/125204Study conducted at Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, and CIEMAT. Equal contribution by Berta Segura-Collar and Blanca Cómitre-Mariano.The lack of response of glioblastoma (GBM) to immunotherapy is closely related to the limited number of T cells in the tumor microenvironment. However, it is still not known why GBM is characterized by an immune-cold tumor microenvironment with reduced CD8+ T-cell infiltration when there is substantial myeloid cell infiltration and a substantial alteration of the blood-brain barrier. The aim of this study was to identify regulators of low CD8+ T-cell infiltration in GBM. Using transcriptomic screening, we found that tribbles homolog 2 (TRIB2) is a regulator of the immune-cold microenvironment characteristic of GBM. Further analysis of a cohort of 114 brain tumors with IHC, RNA sequencing, and qRT-PCR showed that TRIB2 inhibited the transcription of genes involved in antigen presentation by the tumor cells and those involved in T-cell recruitment by modulating the expression of methylation regulators, in particular DNA methyltransferase 1. Further, we observed 75% survival after TRIB2 inhibition in murine glioma models and showed transcriptomic reprogramming by decitabine of genes involved in the processes described above. In our patient-derived tumor fragments assay, we observed a consistent, generalized response to decitabine, suggesting that DNA methyltransferase 1 inhibition (DNMT1) could be a promising therapeutic strategy for GBM.engjournal article2326-6074https://doi.org/10.1158/2326-6066.cir-24-0807metadata only access579.26616.831-006.484+579.26OncologíaNeurociencias (Biológicas)Inmunología3201.01 Oncología2415 Biología Molecular2412 Inmunología3205.07 Neurología