Recent preclinical studies (in vitro and/or in vivo models) exploring TMZ-based therapies in GBM.
| Study title | Description | Year | Mechanism of action/pathway involved | Ref. |
|---|---|---|---|---|
| Evaluation of temozolomide and fingolimod treatments in glioblastoma preclinical models | Preclinical study evaluates the effects of TMZ and fingolimod (an immunomodulatory drug) in GBM 2D and 3D models. | 2023 | Fingolimod inhibits the S1P/S1PR axis, potentially enhancing TMZ efficacy via immune and TME modulation. | [116] |
| Loco-regional treatment with temozolomide-loaded thermogels prevents glioblastoma recurrences in orthotopic human xenograft models | This study investigated the use of TMZ-loaded thermogels for loco-regional treatment in GBM models, aiming to improve drug delivery and therapeutic outcomes. | 2023 | The thermogels provide sustained release of TMZ at the tumor site, potentially improving its efficacy while reducing systemic toxicity. | [117] |
| Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma | Evaluation of the efficacy of combined EGFR and TNF inhibition in an orthotopic murine model of GBM, compared to standard treatment with TMZ. | 2019 | Dual inhibition reduced tumor-promoting inflammation and EGFR signalling, enhancing antitumor immunity. | [118] |
| Piperlongumine conquers temozolomide chemoradiotherapy resistance to achieve immune cure in refractory glioblastoma via boosting oxidative stress-inflamation-CD8+-T cell immunity | Piperlongumine enhances chemoradiotherapy efficacy and overcomes resistance in GBM by promoting anti-tumor immunity. | 2023 | Piperlongumine restores ROS levels reduced by RT/TMZ therapy, activating oxidative stress-related genes and immune responses, while reducing tumor cell proliferation/invasion and increasing apoptosis. | [119] |
| NEO212, temozolomide conjugated to NEO100, exerts superior therapeutic activity over temozolomide in preclinical chemoradiation models of glioblastoma | The molecule NEO212 (TMZ–NEO100 conjugate) showed stronger anticancer activity than single agents in LN229, T98G, U251, and TMZ-resistant LN229TR2 cells (in silico and in vivo). | 2024 | Enhanced DNA damage, reduced MGMT activity; in silico modelling showed enhanced drug delivery and efficacy by targeting tumor-specific pathways. | [120] |
| The Temozolomide–Doxorubicin paradox in Glioblastoma in vitro–in silico preclinical drug-screening | Combined in vitro and in silico screening revealed a paradoxical antagonism between TMZ and doxorubicin in GBM U87MG and primary culture. | 2024 | In silico analysis demonstrates doxorubicin may reduce TMZ cytotoxicity in GBM by enhancing DNA repair and modulating cell cycle progression. | [121] |
| Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma | Preclinical study using patient-derived GBM organoids to model tumor-intrinsic immune programs and progenitor cell populations, enabling evaluation of therapeutic responses including TMZ. | 2024 | Organoids maintain GBM heterogeneity, immune interactions, and stem/progenitor populations, providing a relevant model for testing TMZ efficacy and resistance mechanisms. | [122] |
| Overexpression of miR-124 enhances the therapeutic benefit of TMZ treatment in the orthotopic GBM mice model by inhibition of DNA damage repair | Preclinical study in vitro (GBM cell lines) and in vivo (orthotopic GBM mouse model) showing that miR-124 overexpression improves the therapeutic benefit of TMZ. | 2025 | Inhibition of DNA damage repair via suppression of RAD51, impairing homologous recombination and enhancing TMZ cytotoxicity. | [123] |
S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; RT: radiotherapy; RAD51: molecule in DNA damage repair.
AC: Conceptualization, Writing—original draft, Writing—review & editing. PP: Conceptualization, Writing—original draft, Writing—review & editing, Funding acquisition, Supervision. Both authors read and approved the submitted version.
The authors declare that they have no conflicts of interest.
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This research was funded by the University of L’Aquila, Grants [06VITALITY_PALUMBO]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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