The glioblastoma ecosystem: clonal evolution, heterogeneity, and therapeutic resistance

Therapeutic resistance and recurrence represent major clinical challenges in glioblastoma (GBM), driven by profound tumor heterogeneity and continuous clonal evolution under therapeutic pressure. Conventional diagnostic and therapeutic strategies, which rely on static sampling, struggle to effectively address this dynamic ecosystem. This review synthesizes recent evidence on how single-cell and spatial multi-omics technologies are uncovering the multidimensional complexity of GBM, spanning its diverse cell states, spatial architecture, and clonal dynamics. We dissect the core mechanistic networks driving this evolution, including genomic instability, microenvironmental selection pressures, cellular plasticity, and the integrative role of core signaling pathways. Furthermore, we critically examine the limitations of static diagnostics and propose the pathways through which heterogeneity mediates therapeutic resistance. Given these challenges, future clinical management should ideally transition from a static classification to a dynamic precision paradigm. To this end, we explore the application prospects of dynamic monitoring technologies based on liquid biopsy and radiomics, as well as novel therapeutic strategies aimed at targeting the evolutionary process itself. Ultimately, reconceptualizing GBM as a dynamically evolving ecosystem provides a foundational framework for understanding therapeutic resistance and is pivotal for developing novel strategies that target the evolutionary process itself. However, the clinical translation of this framework faces significant hurdles, including the restrictive blood-brain barrier, technical constraints in longitudinal monitoring, and the complex signaling redundancies that necessitate more adaptive, evolution-informed clinical trial designs. This review suggests a potential path toward a new paradigm of dynamic precision medicine.