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BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma.

BRAF/MEK inhibition induces cell state transitions boosting immune checkpoint sensitivity in BRAFV600E-mutant glioma. Cell reports. Medicine Xing, Y. L., Panovska, D., Park, J. W., Grossauer, S., Koeck, K., Bui, B., Nasajpour, E., Nirschl, J. J., Feng, Z. P., Cheung, P., Habib, P., Wei, R., Wang, J., Thomason, W., Monje, M., Xiu, J., Beck, A., Weber, K. J., Harter, P. N., Lim, M., Mahaney, K. B., Prolo, L. M., Grant, G. A., Ji, X., Walsh, K. M., Mulcahy Levy, J. M., Hambardzumyan, D., Petritsch, C. K. 2025: 102183

Abstract

Resistance to v-raf murine sarcoma viral oncogene homolog B1 (BRAF) plus mitogen-activated protein kinase kinase (MEK) inhibition (BRAFi+MEKi) in BRAFV600E-mutant gliomas drives rebound, progression, and high mortality, yet it remains poorly understood. This study addresses the urgent need to develop treatments for BRAFi+MEKi-resistant glioma using preclinical mouse models and patient-derived materials. BRAFi+MEKi reveals glioma plasticity by heightening cell state transitions along glial differentiation trajectories, giving rise to astrocyte- and immunomodulatory oligodendrocyte (OL)-like states. PD-L1 upregulation in OL-like cells links cell state transitions to immune evasion, possibly orchestrated by Galectin-3. BRAFi+MEKi induces interferon response signatures, tumor infiltration, and suppression of T cells. Combining BRAFi+MEKi with immune checkpoint inhibition enhances survival in a T cell-dependent manner, reinvigorates T cells, and outperforms individual or sequential therapies in mice. Elevated PD-L1 expression in BRAF-mutant versus BRAF-wild-type glioblastoma supports the rationale for PD-1 inhibition in patients. These findings underscore the potential of targeting glioma plasticity and highlight combination strategies to overcome therapy resistance in BRAFV600E-mutant high-grade glioma.

View details for DOI 10.1016/j.xcrm.2025.102183

View details for PubMedID 40505659