GSC State Plasticity Drives Therapeutic Resistance and Recurrence in Glioblastoma

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults, and treatment failure is closely linked to the presence of GBM stem cells (GSCs). Rather than representing a fixed marker-defined state, GSC identity is better understood as a dynamic and reversible stem-like state. GBM cells exhibit transcriptional plasticity, most clearly reflected by the proneural-to-mesenchymal transition, although direct interconversion among neural progenitor cell-like, oligodendrocyte precursor cell-like, astrocyte-like, and mesenchymal-like states remains unproven. GBM cells can also transition bidirectionally between stem-like and differentiated phenotypes, shift between quiescent and proliferative states, and reprogram metabolism in response to nutrient deprivation, hypoxia, and therapy. Perivascular, hypoxic, extracellular matrix, and immunosuppressive niches further regulate these transitions. This plasticity contributes to therapeutic resistance because radiotherapy, temozolomide, and targeted agents can both select preexisting tolerant populations and induce adaptive states. Therapy-persistent GSC-like cells may form residual reservoirs that undergo further remodeling and contribute to recurrence. Emerging strategies, most still preclinical, aim to destabilize stem-like states, broaden coverage across heterogeneous GSC populations and protective niches and block therapy-induced adaptive transitions. Thus, constraining GSC state plasticity may provide a framework for overcoming therapeutic resistance and recurrence in GBM.