Promising targets to overcome radioresistance in glioblastoma: current status and future perspectives.

Abstract

Purpose: GBM remains refractory to standard radiotherapy. Resistance to IR arises from complex molecular and cellular interactions and signaling pathways. Robust DDR restores lethal and sublethal DNA breaks and limits IR cytotoxicity. These responses can be potentiated by other mechanisms, such as hypoxia, enhanced antioxidant networks, and dysregulated tyrosine kinases. These factors sustain survival signaling and promote cell cycle progression after irradiation. The immune milieu is a key factor that amplifies resistance through cellular interactions. TAMs, MDSCs, and their co-inhibitory signaling pathways are key mediators of immunosuppressive stroma that exhaust anticancer immune cells, providing a way for tumor growth and metastasis. All these cellular and molecular interactions can stimulate resistance of GBM to IR. Therefore, targeting these resistance mediators in combination therapy approaches can produce stronger and more durable effects.

Conclusions: This article overviews preclinical and clinical studies with a focus on promising combination modalities with radiotherapy for radiosensitizing GBM. In this review, we suggest that targeting some immunomodulators, hypoxia, DNA damage pathways, cancer stemness, altered metabolism, and redox responses can sensitize GBM to radiotherapy. In addition, we provide evidence that effective radiosensitization strategies should be guided by tumor genotype and other biomarker status.