The Paradox of Senescence in Glioblastoma: SASP as an Emerging Cancer Hallmark

Cellular senescence has been traditionally viewed as a tumor-suppressive program that halts its proliferation in response to oncogenic stress or DNA damage. However, recent studies have highlighted a paradoxical role for senescence in glioblastoma (GBM), IDH-wildtype, the most aggressive primary brain tumor in adults. Accumulating evidence indicates that senescence represents a "frequent and durable" cell fate in GBM, particularly following standard therapies such as temozolomide and radiotherapy. Senescent cells frequently persist after temozolomide or radiotherapy and acquire a senescence-associated secretory phenotype (SASP) composed of inflammatory cytokines, growth factors and matrix-remodeling enzymes. These factors not only promote tumor cell survival with stemness-induction but also reshape the pro-tumorigenic microenvironment with metabolic rewiring and immune evasion. Notably, senescence also arises in non-malignant cells-including astrocytes, endothelial cells, microglia, and infiltrating immune cells-creating a multicellular senescent niche that fuels recurrence. Here, we describe a recent advance in our understanding of senescence and SASP in the pathobiology of GBM. We further focus on a state-of-the-art, challenging exploration of the idea that single-cell and spatial profiling, capable of identifying senescence- and SASP-associated morphologic and heterogeneous states, will further refine patient selection and therapeutic timing. By reframing senescence as a modifiable determinant of GBM evolution, this review underscores its emerging significance as both a cancer hallmark and a therapeutic vulnerability.