Cellular responses to targeted radionuclide therapy: rethinking radiobiology under continuous low dose rates.

Targeted radionuclide therapy (TRT) delivers ionizing radiation directly to cancer cells through radio molecules that bind tumor-associated targets. Clinically successful examples include somatostatin receptor-directed TRT for neuroendocrine tumors, and prostate specific membrane antigen-targeted TRT for prostate cancer. Despite these advances, therapeutic efficacy remains limited by sublethal tumor doses, heterogeneous intratumoral uptake, and intrinsic radioresistance. A major challenge in improving TRT is the continued reliance on radiobiological concepts derived from external beam radiotherapy (EBRT). In contrast to EBRT, TRT is characterized by prolonged exposure times, low and variable dose rates, heterogeneous energy deposition, and radiation qualities ranging from low-linear energy transfer (LET) β-- particles to high-LET α-particles, resulting in distinct biological stress profiles that cannot be fully predicted from EBRT-based knowledge. This review summarizes the radiobiological properties that distinguish TRT from EBRT and describes how these features influence DNA damage induction and downstream cellular stress responses. Key cellular outcomes, including apoptosis, senescence, and alternatively regulated cell death pathways are discussed in relation to how dose rate kinetics and LET affect their timing and magnitude. By integrating concepts from radiation physics, DNA damage signaling, and cell fate mechanisms, this review highlights areas where mechanistic understanding remains limited and points to opportunities for refining TRT. A deeper understanding of these processes will support rational treatment design and help develop strategies that enhance tumor sensitivity while minimizing normal-tissue toxicity.