GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301111/primary200OKTranscriptomics Mus musculusHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301111GEOGSEfalseDissecting cellular state alterations critical for the synergistic response and therapy resistance of the combined Abemaciclib, Temozolomide, and Radiation in DIPG PDOX modelsDiffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain cancer. Here, we demonstrated that combining the CDK4/6 inhibitor abemaciclib with temozolomide and radiation (the triple therapy) yields synergistic anti-tumor effects in DIPG organoids and significantly extends survival times in patient-derived orthotopic (intra-brain stem) xenograft (PDOX) models. Mechanistically, we performed scRNA-seq and identified dynamic reprogramming of tumor cell states, including the expansion of NPC-like, depletion of OPC- and AC-like subpopulations, and persistence of MES-like and mitotic-like cells, that contributed to therapeutic resistance. Pseudotime trajectory analysis further revealed therapy-induced cell fate transitions within NPC- and OPC-like compartments, including the enrichment of stem-like cells. More importantly, we discovered that an alternative trajectory—exit from stemness toward more differentiated states—may also contribute to therapeutic failure. Additionally, we identified a novel radiation-resistant subpopulation and found a new set of transcriptional targets indicative of therapeutic vulnerability. This study demonstrated the triple therapy as a promising DIPG regimen that can be rapidly translated into clinical trials and nominated new cellular and molecular targets to overcome residual disease.2026/08/07GSE301111GSM9075552GSM9075553GSM9075542GSM9075543GSM9075554GSM9075544GSM9075555GSM9075550GSM9075551GSM9075549GSM9075545GSM9075546GSM9075547GSM90755483428434290301111 Mus musculusHomo sapiens[42532370]