Alpha particle therapy in glioblastoma: emerging biomarkers, mechanisms of response, and translational opportunities.

Glioblastoma remains the most aggressive primary malignant brain tumor in adults. Disease progression is driven by multiple biological mechanisms, including glioma stem cell persistence, intratumoral heterogeneity, hypoxia-associated treatment resistance, enhanced DNA damage repair, immune evasion, and dynamic interactions within the tumor microenvironment. These factors contribute to therapeutic failure and highlight the need for novel treatment strategies and biomarker-driven approaches guiding patient selection and response assessment. Alpha particle therapy is a promising modality due to it's high linear energy transfer (LET), short tissue range, and potent relative biological effectiveness (RBE), inducing complex DNA damage that is difficult to repair while limiting radiation exposure to surrounding normal tissue. Among emerging platforms, Diffusing Alpha-emitters Radiation Therapy (Alpha DaRT) enables sustained intratumoral delivery of alpha-emitting radionuclides, while targeted alpha therapies employ tumor-specific radiopharmaceuticals to selectively deliver highly cytotoxic radiation to malignant cells. Beyond direct tumor cell killing, accumulating evidence suggests alpha particle therapy targets several biological pathways implicated in glioblastoma progression, including DNA damage response signaling, glioma stem cell survival, hypoxia-driven adaptation, and immune suppression. These mechanisms generated growing interest in the identification of predictive and pharmacodynamic biomarkers capable of guiding treatment selection and monitoring therapeutic response. Candidate biomarkers include DNA repair-associated proteins, stemness-related markers, molecular alterations such as MGMT and IDH status, liquid biopsy analytes, and advanced imaging biomarkers. In this review, we summarize current alpha-emitting therapeutic strategies for glioblastoma, with particular emphasis on Alpha DaRT, and discuss emerging biological mechanisms of response, biomarkers associated with tumor progression and therapeutic sensitivity, and opportunities for biomarker-guided clinical implementation.