Chromosomal Instability Drives Glioblastoma Heterogeneity and Therapeutic Opportunities

ABSTRACT Glioblastoma, the most aggressive and lethal form of brain cancer, is defined by profound genomic instability, with Chromosomal Instability (CIN) playing a central role in driving tumor progression, therapy resistance, and poor prognosis. CIN is characterized by numerical and structural alterations, is driven by mechanisms such as mitotic errors, centrosome amplification, spindle assembly checkpoint dysfunction, and defective DNA repair pathways. These aberrations contribute to tumor heterogeneity, leading to the emergence of Glioblastoma Stem Cells (GSCs) with enhanced plasticity, therapy resistance, and metastatic capacity. Chromothripsis, frequently involves specific chromosomes and stems from micronuclei rapture, resulting in chromosomal rearrangement. The immune implications of CIN are also critical, with the Cyclic GMP–AMP Synthase–Stimulator of Interferon Genes (cGAS‐STING) pathway toggling between anti‐tumor immunity and immune evasion. Therapeutic strategies targeting CIN are explored, including inhibitors of centrosomal clustering, DNA damage response pathways, and spindle assembly components, as well as innovative approaches like Chimeric Antigen Receptor T (CAR‐T) cell therapies and nanoparticle‐based drug delivery systems. Advances in single‐cell sequencing provide transformative insights into CIN‐driven glioblastoma heterogeneity and therapeutic vulnerabilities. By integrating mechanistic understanding with translational strategies, this review underscores CIN as both a therapeutic challenge and an opportunity, charting a path toward improving glioblastoma treatment outcomes and patient survival.