From protection to progression: How CCT/TRiC shapes therapy-induced senescence in glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor despite maximal resection, radiotherapy, and temozolomide. Growing evidence indicates that standard therapies drive many GBM cells into therapy-induced senescence (TIS), marked by permanent proliferation arrest, high metabolic activity, and the senescence-associated secretory phenotype (SASP). Although senescent cells may initially limit growth, their persistence can fuel recurrence by altering the microenvironment while driving immunosuppression and stem-like traits. GBM is also "chaperone dependent," relying on proteostasis networks for rapid growth, invasion, and treatment resistance. The eukaryotic chaperonin CCT/TRiC, an ATP-dependent complex of eight subunits (CCT1-CCT8), is essential for folding actin and tubulin and for the maturation of multiple oncogenic clients. We review recent findings on CCT/TRiC subunit dysregulation in GBM and propose a mechanistic link between chaperonin activity and senescence, integrating p53/p21 and p16INK4a/Rb signaling, EGFR-driven survival, hypoxia/HIF-mediated metabolic reprogramming, and immune infiltration in high-SASP tumors. We discuss how CCT/TRiC is probably involved in maintaining glioma stem cell (GSC) proteostasis by modulating EGFR, TGF-β, mTOR, Wnt/β-catenin, and Notch pathways, thereby supporting GSC survival, self-renewal, and invasiveness. We also propose how CCT/TRiC inhibition can lead to impaired macroautophagy by disrupting mTOR signaling-both crucial for sustaining senescence and SASP-thereby compromising proteostasis and autophagic flux. Finally, we outline possible therapeutic strategies based on this axis, including novel combinations of senolytics, immunotherapy potentiators, and CCT/TRiC-targeted agents to prevent SASP-driven progression and relapse.