Glioblastoma under chemotherapy pressure: interconnected tumor-cell adaptations shaping tumor behaviour and resistance.

Abstract

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains largely incurable because of its marked cellular heterogeneity, limited drug delivery, and rapid development of resistance to temozolomide (TMZ). Beyond its cytotoxic activity, TMZ induces genotoxic and oxidative stress and exerts strong selective pressure, potentially promoting adaptive states in GBM cells that survive chemotherapy. These adaptive responses are heterogeneous and context-dependent and may not only promote tumor cell intrinsic resistance but also strongly reshape the surrounding tumor microenvironment. This review focuses on residual tumor cells that survive TMZ-induced stress and examines how their adaptive responses contribute to treatment resistance and may be sustained by reciprocal interactions with the tumor microenvironment. Specifically, it integrates findings on stem-like enrichment, inflammatory and redox signalling, altered extracellular vesicle release, therapy-induced senescence, and extracellular matrix remodelling, examining how these processes may reinforce one another and link tumor cell survival to signals that influence neighbouring malignant and non-malignant cells. Findings are interpreted within their experimental context, distinguishing evidence from in vitro studies, animal models, and patient samples. This integrated framework provides a rationale for investigating TMZ-based strategies aimed not only at eliminating surviving GBM cells but also at limiting their ability to promote a microenvironment that supports tumor persistence and resistance.