Cellular senescence in glioblastoma (WHO Grade IV) is not the tumor-suppressive endpoint it represents in normal tissue. In malignant gliomas, senescence bifurcates into therapy-induced senescence (TIS) and spontaneous senescence (SS), each generating phenotypically, functionally, spatially, and temporally distinct cellular populations. Key molecular drivers include dysregulation of EGFR, PI3K-AKT, and MAPK oncogenic signaling, alongside epigenetic reprogramming and metabolic rewiring. The senescence-associated secretory phenotype (SASP) emerges as the critical mechanism linking senescent glioma cells to microenvironmental remodeling and non-cell-autonomous therapy resistance.
This review reframes a long-standing assumption: that inducing senescence in cancer cells is therapeutically beneficial. In GBM — one of the most treatment-refractory malignancies with a median survival under 15 months — TIS appears to generate senescence-like states that paradoxically enable tumor recurrence through SASP-mediated immune evasion, stromal reprogramming, and paracrine pro-survival signaling to neighboring tumor cells. This mirrors findings in breast and lung cancers, where TIS has been linked to chemoresistance via IL-6 and IL-8 secretion. The emerging therapeutic logic — combining senolytics (clearing senescent cells) with senomorphics (suppressing SASP) alongside standard chemoradiation — is biologically coherent but lacks robust clinical validation in neuro-oncology. As a review, this paper synthesizes rather than generates primary data, but its conceptual reframing of glioma senescence as a driver of heterogeneity rather than a static endpoint is editorially significant and clinically urgent.