Radiotherapy resistance in glioblastoma: Mechanistic insights and novel therapeutic approaches (Review).

Glioblastoma (GBM) is currently the most lethal type of primary brain tumor, with a median survival time of 15‑20 months despite the use of multimodal therapy. Although radiotherapy (RT) remains a cornerstone of GBM treatment, a subset of patients who initially respond to RT eventually acquire resistance, leading to tumor relapse. The emergence of radioresistance severely impairs the long‑term efficacy of RT, highlighting the importance of understanding its underlying mechanisms. The present review synthesizes emerging evidence that therapy‑induced remodeling of the blood‑brain barrier (BBB), upregulation of ATP‑binding cassette efflux transporters, hypoxia‑driven hypoxia inducible factor‑1α signaling and tumor microtube (TM)‑mediated intercellular communication converge to create a self‑reinforcing resistance network. These interconnected mechanisms collectively drive adaptive radioresistance, rather than acting in isolation. Based on this framework, the present review evaluates therapeutic strategies designed to disrupt distinct nodes of this network, including epigenetic modulators, poly (ADP‑ribose) polymerase inhibitors, BBB‑penetrant agents and TM‑targeting approaches, such as connexin43 peptide inhibitors and high‑linear energy transfer particle therapy. The clinical implications of these findings are discussed, with emphasis on biomarker‑driven patient stratification and combinatorial regimens that concurrently target multiple resistance mechanisms.