Rewiring cell death and evading repair: Evolution of temozolomide and emerging strategies against resistant glioblastoma.

Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor, characterized by a universally dismal prognosis. For over two decades, the alkylating agent temozolomide (TMZ) has remained the cornerstone of the standard-of-care "Stupp protocol" largely owing to its unique pH-dependent activation and favorable blood-brain barrier penetration. However, the clinical efficacy of TMZ is profoundly compromised by complex intrinsic and acquired resistance mechanisms. These are primarily driven by O6-methylguanine-DNA-methyltransferase (MGMT) overexpression, mismatch repair (MMR) deficiency, and hyperactive base excision repair (BER) pathways. In this review, the chemical properties and classical cytotoxic mechanisms of TMZ are comprehensively summarized, followed by a systematic exploration of emerging medicinal chemistry strategies designed to overcome this multifaceted resistance. Specifically, recent advances in circumventing MGMT-mediated repair through epigenetic modulation and targeted protein degradation are highlighted. Furthermore, we discuss the rational structural modifications of the imidazotetrazine scaffold to induce steric hindrance, alongside a paradigm shift toward rewiring cell death mechanisms-such as transitioning from DNA monomethylation to interstrand cross-linking (ICLs) and the activation of non-apoptotic pathways, including ferroptosis and autophagy. Finally, systemic interventions exploiting "BRCAness"-induced synthetic lethality via PARP inhibitors are examined, culminating in future perspectives on the integration of artificial intelligence (AI) and spatiotemporally responsive nanocarriers for the design of next-generation anti-GBM therapeutics.