The reprogramming impact of SMAC-mimetic on glioblastoma stem cells and the immune tumor microenvironment evolution

In order to comprehensively assess the impact of Xevinapant on the cellular and molecular heterogeneity of the TME, we employed 10X Genomics single-cell RNA sequencing (scRNA-seq) to investigate the modulation impact of Xevinapant on GBM TME. In this study, we sought to further investigate and characterize the anti-tumor and immune TME-modulating impacts of Xevinapant in human and murine GBM models at the single-cell level. We also evaluated associated mechanisms of therapeutic resistance and therapeutic synergy to Xevinapant in GBM. Our study, which represents the first comprehensive characterization of the impact of Xevinapant on the GBM TME repertoire demonstrates robust anti-tumor activity and favorable immune modulation of the TME, all highly supportive for further clinical investigation of Xevinapant in GBM. We developed Trp53+/- and Nf1+/- mGSC orthotopic model in C57BL/6J mice and treated them with either vehicle control or Xevinapant daily. Cells for sequencing were isolated from these orthotopic tumors (4 from each group) right after treatment.