Exploring the therapeutic potential of localized alpha irradiation for cancer: from DNA damage to immune activation

Alpha radiation has emerged as a promising modality in cancer treatment due to its unique physical and biological properties. Among these, diffusing alpha-emitters radiation therapy (DaRT) delivers alpha radiation directly into solid tumours using inserted seeds. This review synthesizes both the biological mechanisms and therapeutic implications of alpha irradiation, with a focus on DaRT. We explore how alpha particles induce complex DNA damage, modulate the tumour microenvironment, and interact with immune therapies. Emphasis is placed on preclinical and early clinical findings that suggest DaRT's potential to improve outcomes, especially in difficult-to-treat malignancies. The high linear energy transfer (LET) radiation induces complex DNA damage in tumour cells, leading to increased cell death compared to conventional radiotherapy. Alpha particles have a short range in tissue, allowing for highly localized treatment with minimal damage to surrounding healthy tissue. Recent studies have demonstrated that alpha radiation can stimulate antitumor immune responses, potentially enhancing treatment efficacy. Clinical trials utilizing alpha-emitting radioisotopes have shown encouraging results in various cancer types, particularly for metastatic disease.