Temozolomide resistance in glioblastoma: Multidimensional networks, core signaling hubs, and targeted therapeutic strategies.

Glioblastoma (GBM) represents the most aggressive primary malignant tumor of the adult central nervous system, with an extremely poor clinical prognosis. As the first-line chemotherapeutic agent for GBM, temozolomide (TMZ) has encountered a critical therapeutic bottleneck due to the development of drug resistance in tumor cells. GBM pathogenesis is jointly driven by multiple factors, including genetics, epigenetics, and the tumor microenvironment. O6-methylguanine-DNA methyltransferase (MGMT) -driven repair of DNA alkylation lesions is the central molecular mechanism underlying TMZ resistance in GBM. Beyond this canonical pathway, the maintenance of stemness in glioma stem cells (GSCs), the bidirectional regulation of autophagy, metabolic reprogramming that reshapes redox homeostasis, and multicellular crosstalk in the tumor microenvironment also contribute to the development of drug resistance. Core molecules such as signal transducer and activator of transcription 3 (STAT3), 5'-AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) interact to form an intricate signaling network that modulates drug resistance. This review systematically illustrates the regulatory networks governing GBM pathogenesis and TMZ resistance. It dissects signaling cascades of distinct resistance mechanisms and crosstalk between core signaling axes, and identifies key regulatory molecules and druggable targets for each resistance phenotype. It aims to provide a theoretical basis and novel insights for the development of emerging therapeutic strategies, including targeted therapy, immunomodulation, combination therapy, and nanodrug delivery, thereby promoting the establishment of multi-targeted and individualized precision medicine models and laying a foundation for breaking through the bottleneck of GBM chemoresistance and improving the survival prognosis of patients.