BRAF/MEK Inhibition Induces Cell State Transitions Boosting Immune CheckpointSensitivity in BRAFV600E-mutant Glioma

Resistance to BRAF plus 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 in novel 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 tumor 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-wildtype 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 HGG. In briefXing et al. show that combined BRAF and MEK inhibitor (BRAFi+MEKi) treatment induces cell state transitions in BRAFV600E-mutant high-grade glioma cells linked with programmed death-ligand (PD-L1) upregulation and T cell suppression, potentially orchestrated through the secretion of galectin-3. These tumor-intrinsic adaptations may be overcome by concurrent immune checkpoint inhibition (ICI), as demonstrated in murine studies, offering novel therapeutic opportunities. HighlightsO_LIBRAFV600E-mutant HGG exhibits cell plasticity induced by BRAFi+MEKi, which links cell state transitions towards glial differentiation with immune evasion C_LIO_LIBRAFi+MEKi enhances anti-tumor immunity and simultaneously suppresses T cells via PD-L1 upregulation C_LIO_LIBRAF-mutant glioblastoma has elevated PD-L1 expression compared to BRAF-wildtype counterparts, providing a criterion for PD-1 inhibition therapy C_LIO_LIConcurrent BRAFi+MEKi and immune checkpoint inhibition enhance T cell-mediated anti-tumor activity and boost survival more effectively than sequential treatment in mice, guiding clinical translation C_LI