Radiopharmaceutical therapy in cancer: clinical momentum, biological complexity, and the next era of precision systemic radiation oncology

Radiopharmaceutical therapy has evolved from organ-seeking and antibody-based treatments into a precision-oncology discipline integrating molecular imaging, target selection, radionuclide therapy, dosimetry, and multidisciplinary care. Established agents include radioiodine for differentiated thyroid cancer, high-specific-activity 131 I-MIBG for advanced pheochromocytoma and paraganglioma, 90 Y microsphere radioembolization for selected hepatic malignancies, [ 177 Lu]Lu-DOTATATE for somatostatin receptor-positive neuroendocrine tumors, [ 177 Lu]Lu-PSMA-617 for PSMA-positive metastatic prostate cancer, and 223 Ra for bone-predominant metastatic castration-resistant prostate cancer. These successes also expose a central challenge: the same administered activity can yield markedly different tumor and normal-organ absorbed doses, and therefore different biological effects, across patients and lesions. Tumor uptake and retention, lesion heterogeneity, radionuclide emissions, organ-at-risk exposure, marrow reserve, and treatment logistics together determine the therapeutic index. Development is extending beyond PSMA and SSTR to FAP, CXCR4, B7-H4, Trop-2, CAIX, GRPR, DLL3, and HER2, while alpha emitters such as 225 Ac and 212 Pb and emerging radiometals such as 161 Tb and matched 203 Pb/ 212 Pb systems are being evaluated for disease incompletely controlled by established beta emitters. Adaptive dosimetry, RPT-specific radiobiology, molecular imaging, and rational combination strategies are increasingly central to trial design. This review examines the clinical momentum, biological complexity, translational barriers, and implementation requirements that will determine whether radiopharmaceutical therapy becomes a generalizable form of precision systemic radiation oncology.