Glioblastoma cell plasticity: A new paradigm in glioblastoma therapeutic resistance

For glioblastoma (GBM), therapeutic resistance shows a formidable obstacle to effective treatment. Recent insights into cellular plasticity as a novel paradigm for understanding this resistance suggest that tumor cells undergo phenotypic and molecular alterations during GBM progression, collectively termed cellular plasticity. These alterations arise from complex tumor microenvironment (TME) factors, epigenetic changes, and selective pressures induced by radiotherapy or temozolomide (TMZ), ultimately leading to significant tumor heterogeneity and therapeutic resistance. This review will examine the formation of GBM cell plasticity (GCP) and its manipulative mechanisms in therapeutic resistance. GCP arises from the integrated interaction between intrinsic epigenetic and transcriptional reprogramming and extrinsic TME signals, enabling GBM cells to flexibly transition between multiple states. These transitions are not random but constitute an adaptive evolutionary network for therapeutic resistance. We summarize the intrinsic and extrinsic mechanisms driving GCP and promoting the development of therapeutic resistance. Simultaneously, we systematically explore emerging therapeutic strategies targeting GCP, such as inhibiting or reversing GCP by targeting specific signaling pathways. Currently, multiple clinical trials worldwide are underway to improve GBM treatment resistance, spanning cutting-edge fields including targeted therapeutics and immunotherapy. These advances provide crucial directions for developing novel treatment modalities and combination therapies targeting GCP within the context of treatment resistance.