ABSTRACT Glioblastoma (GBM) is a highly aggressive, therapy‐resistant brain tumor with inevitable recurrence despite maximal multimodal treatment. Increasing evidence suggests that this intractability arises from coordinated cellular programs rather than a single dominant pathway. Central to these programs are glioma stem‐like cells (GSCs), which sustain self‐renewal, phenotypic plasticity, and resistance to genotoxic and metabolic stress, and yet the molecular basis of their long‐term tumor‐propagating capacity remains incompletely understood. Here, we synthesize recent advances to propose an integrated conceptual framework—the Triadic Nexus—in which GSC stemness, telomere maintenance mechanisms, and metabolic reprogramming function as a self‐reinforcing regulatory system. We review how telomerase reactivation versus alternative lengthening of telomeres (ALT) differentially shape genomic stability, immune signaling, and metabolic states and how metabolic plasticity feeds back to regulate stemness and telomere‐associated stress responses. Drawing on single‐cell, spatial, and multi‐omics studies, we highlight how these interdependent axes collectively sustain therapy resistance and tumor recurrence. Finally, we discuss the translational implications of the Triadic Nexus, emphasizing rational combinatorial therapeutic strategies and biomarker‐guided patient stratification based on telomere and metabolic signatures. By unifying stemness, telomere biology, and metabolism into a mechanistically testable model, this review provides a systems‐level framework for understanding GBM persistence and guiding next‐generation therapeutic interventions.
Sung et al. (Mon,) studied this question.