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

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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.

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