Radiation-Induced Senescence in Radiopharmaceutical Therapy: Mechanisms and Therapeutic Implications

Radiopharmaceutical therapy (RPT) has emerged as a radiation therapy modality with the distinctive ability to systemically treat metastatic disease by targeting specific biologic features expressed on cancer cells. Although the radiobiology of RPT remains incompletely understood, the low absorbed dose rates associated with RPT render these treatments prone to sublethal radiation damage, leading to alternative cell fates, such as senescence. In oncology, senescence-a stable state of proliferative cellular arrest-has been shown to act as a double-edged sword, providing both protumor and antitumor effects. The role of senescence in radiation therapy is of increasing interest as a mechanism of treatment resistance that, if targeted, may enhance tumor control and improve long-term treatment outcomes. Most current literature has focused on senescence induced by external beam radiation therapy, with few reports examining its role in the context of RPT. To our knowledge, this is the first review to contextualize RPT radiobiology within the molecular underpinnings of senescence, consolidate existing evidence, and propose a framework that recognizes RPT as an intrinsically senogenic radiation modality. Further, this review discusses opportunities for the combination of senescence-targeting drugs ("senotherapeutics") with RPT as a means of enhancing treatment efficacy by tackling the radiation-induced senescent burden and minimizing the deleterious effects of senescence.