Rethinking glioma-associated senescence: Drivers of heterogeneity and therapeutic resistance

Cellular senescence, traditionally defined as a stress-induced irreversible cell-cycle arrest program with tumor-suppressive functions in normal somatic cells, exhibits remarkable heterogeneity in malignant gliomas, particularly in glioblastoma (GBM, WHO grade IV). Glioma-associated senescence represents a dynamic and context-dependent cellular state rather than a uniform endpoint and can be broadly categorized into therapy-induced senescence (TIS) and spontaneous senescence (SS) based on induction mechanisms. The phenotypic and functional heterogeneity of glioma-associated senescence is a key driver of intratumoral complexity, adaptive tumor survival, and resistance to conventional glioma therapies, and engages in bidirectional crosstalk with the brain tumor microenvironment to modulate disease progression. In this review, we rethink the current understanding of the core characteristics and multi-dimensional heterogeneity of glioma-associated senescence, including phenotypic, functional, spatial and temporal heterogeneity. We further elaborate on the critical molecular drivers underlying glioma-associated senescence heterogeneity, encompassing alterations in core cell-cycle regulatory pathways, dysregulation of oncogenic signaling including epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/protein kinase B (PI3K-AKT), and mitogen-activated protein kinase (MAPK) pathways, epigenetic modifications, metabolic reprogramming, and the regulatory role of the tumor microenvironment. We also discuss the senescence-associated secretory phenotype (SASP) as a core functional feature of senescent or senescence-like glioma cells, its composition and functional heterogeneity, and its pivotal role in remodeling the glioma microenvironment and mediating non-cell-autonomous effects in therapy resistance. Additionally, we analyze the dual role of TIS in glioma treatment and the mechanisms by which TIS-associated senescence-like states may contribute to tumor recurrence. Finally, we outline emerging senescence-targeted therapeutic strategies, including senolytics and senomorphics, as well as optimized combination regimens with conventional therapies, and highlight the challenges and future perspectives in translating these strategies into clinical practice. This review aims to provide a comprehensive framework for understanding the biological significance of glioma-associated senescence heterogeneity and to guide the development of innovative precision interventions to overcome therapy resistance and improve clinical outcomes for glioma patients.