temozolomide

Overview

Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent widely used in the treatment of malignant brain tumors, most notably glioblastoma multiforme (GBM) and other high-grade gliomas. It belongs to the imidazotetrazine class of compounds and exerts its cytotoxic effect by methylating DNA at the O6 position of guanine, leading to DNA strand breaks, replication failure, and apoptosis in rapidly dividing tumor cells. The drug's ability to cross the blood-brain barrier makes it particularly valuable in neuro-oncology, where it remains a cornerstone of the Stupp protocol — concurrent (chemo)radiotherapy followed by adjuvant TMZ cycles — established as standard of care for newly diagnosed GBM. Beyond gliomas, temozolomide is also employed in combination regimens for pediatric solid tumors, including neuroblastoma and Ewing sarcoma, reflecting its broad alkylating activity and manageable tolerability profile.

A central challenge in temozolomide-based therapy is the development of tumor resistance, which is mechanistically linked to the expression and methylation status of the MGMT promoter. MGMT (O6-methylguanine-DNA methyltransferase) directly repairs the DNA lesions induced by TMZ; tumors with an unmethylated MGMT promoter tend to express this repair enzyme at high levels, rendering TMZ less effective. Abnormal DNA damage repair pathways — including those driven by oncogenic alterations such as EGFRvIII — further complicate treatment outcomes. As a result, understanding and overcoming TMZ resistance has become one of the most active areas of contemporary neuro-oncology research.

Focus of Latest Publications

Recent publications on temozolomide have focused largely on overcoming resistance in glioblastoma and on identifying biomarkers that may predict response to DNA-damaging therapy. Several studies examined temozolomide in combination strategies, including adjuvant use with a neuronal nitric oxide synthase inhibitor (BA-101), synergy with rutin in YANK2-overexpressing glioblastoma models, and incorporation into localized chemo-photothermal delivery systems using MXene-integrated GelMA microspheres. Across these reports, temozolomide was generally positioned as a standard cytotoxic backbone whose activity might be enhanced by targeted agents, drug delivery platforms, or biomarker-guided combinations.

Mechanistic work highlighted molecular determinants of temozolomide resistance in glioblastoma. One study reported that MET-mediated phosphorylation of YANK2 promoted glioblastoma cell proliferation and tumor growth, and that rutin directly bound YANK2 and synergized with temozolomide to suppress tumor growth and prolong survival in orthotopic models. Another study found that inhibition of miR-25-3p in patient-derived glioblastoma cells reduced β-catenin signaling, re-induced FBXW7 expression, and increased temozolomide sensitivity in a subset of cell lines, with accompanying reductions in invasiveness and a shift toward a less aggressive transcriptional and epigenetic state. A separate publication linked the cuproptosis-related protein SLC31A1 to the immune microenvironment of glioblastoma and specifically evaluated whether cuproptosis agonists could alter temozolomide sensitivity.

Temozolomide was also evaluated in other tumor contexts as a marker of sensitivity to DNA damage-based treatment. In nasopharyngeal carcinoma, SLC44A4 overexpression was associated with reduced malignant behavior and increased sensitivity to temozolomide, along with other DNA-damaging agents such as doxorubicin, cisplatin, olaparib, and etoposide. In a pediatric H3K27M-mutant diffuse intrinsic pontine glioma study, the role of adding temozolomide to radiotherapy was examined, reflecting ongoing uncertainty about the benefit of chemoradiotherapy in this disease. Additional clinical and translational reports included retrospective evaluation of adjuvant temozolomide in high-risk WHO grade 2 diffuse glioma and broader combination regimens such as capecitabine and temozolomide in neuroendocrine tumors, or bevacizumab, irinotecan, and temozolomide in relapsed/refractory neuroblastoma.

Overall, the recent literature portrays temozolomide as a central therapy whose limitations are driven by intrinsic and acquired resistance, especially in glioblastoma. Current investigations emphasize combination approaches, biomarker stratification, and resistance pathways involving MET-YANK2 signaling, miR-25-3p/β-catenin, DNA damage repair, and cuproptosis-related biology. Several studies also suggest that delivery optimization and local treatment platforms may improve the therapeutic impact of temozolomide-based regimens.

Key Publications

• NEWJul Targeting Temozolomide-Resistant Glioblastoma: Therapeutic Potential of Neuronal Nitric Oxide Synthase Inhibitor. (Cancer medicine, 2026, PMID 42374654): "The treatment of glioblastoma remains a major clinical challenge, largely due to intrinsic and acquired resistance to Temozolomide (TMZ)."
• NEWJun Downregulation of SLC44A4 in nasopharyngeal carcinoma is associated with malignant progression, B-cell/TLS-related immune features, and sensitivity to DNA-damaging agents. (PloS one, 2026, PMID 42361082): "SLC44A4 overexpression also increased sensitivity to DNA-damaging agents, including temozolomide, doxorubicin, cisplatin, olaparib, and etoposide, while decreasing sensitivity to 5-fluorouracil."
• NEWJun MET-mediated phosphorylation of YANK2 at Y282 inhibits NEDD4L-dependent SUMOylation and degradation, promoting chemoresistance in glioblastoma. (Molecular biomedicine, 2026, PMID 42337173): "Importantly, rutin exhibits synergistic effects with temozolomide (TMZ), significantly inhibiting tumor growth and prolonging survival in YANK2 overexpressing orthotopic glioma models."
• NEWJun Dual-functional MXene-integrated GelMA microspheres for synergistic chemo/photothermal therapy: In vitro 2D/3D multi-cancer evaluation and in vivo breast cancer validation. (International journal of biological macromolecules, 2026, PMID 42251874): "Temozolomide (TMZ) or doxorubicin (DOX) were first loaded onto MXene-SP and subsequently encapsulated into GelMA microspheres through a flow-focusing microfluidic platform, resulting in highly uniform and size-controlled drug delivery systems."
• Jun Efficacy of chemoradiotherapy in pediatric H3K27M-mutant diffuse intrinsic pontine glioma: a study based on single-center and SEER data. (Journal of neuro-oncology, 2026, PMID 42218248): "the survival benefit of adding temozolomide (TMZ) remains controversial."
• Jun Hsa-miR-25-3p Inhibition Sensitizes Patient-Derived Glioblastoma Cells to Temozolomide via β-catenin Downregulation. (Cellular and molecular neurobiology, 2026, PMID 42218313): "...and resistance to temozolomide (TMZ)."
• Jun Implications of the Cuproptosis Protein SLC31A1 for the Immune Microenvironment and Temozolomide Sensitivity in Glioblastoma. (Anticancer research, 2026, PMID 42203322): "This study aimed to investigate the distribution of the cuproptosis-related key protein SLC31A1 in the immune microenvironment of glioblastoma (GBM) and to evaluate the effect of cuproptosis agonists on temozolomide (TMZ) sensitivity."
• May Comprehensive quantum chemical analysis, vibrational spectroscopy, molecular docking, ADMET, and in vitro validation studies of hydroxychloroquine-MRGPRX2 complex in IDH-wildtype glioblastoma. (PloS one, 2026, PMID 42166475): "Comparative docking with the standard therapeutic Temozolomide (TMZ) yielded a lower affinity of -5.6 kcal/mol."
• May Treatment patterns and outcomes in high-risk WHO grade 2 diffuse glioma: a multicentre retrospective cohort study. (Journal of neuro-oncology, 2026, PMID 42159820): "...following radiotherapy with adjuvant temozolomide (TMZ) or procarbazine, lomustine, and vincristine (PCV)..."
• Jun [177Lu]Lu-DOTATATE PRRT and CAPTEM chemotherapy for pancreas and small bowel neuroendocrine tumours: The AGITG CONTROL NETS Multi-centre randomized trial. (European journal of cancer (Oxford, England : 1990), 2026, PMID 42142431): "To evaluate the efficacy of [177Lu]Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) plus capecitabine and temozolomide (CAPTEM) in participants(pts) with progressive WHO Grade 1-2 neuroendocrine tumours: pancreas(pNETs) and small bowel(SBNETs)."