Emerging role of radiopharmaceutical therapy in oncology: advances, challenges, and future directions.

Radiopharmaceutical therapy has transformed cancer management by enabling systemic delivery of ionizing radiation via molecularly targeted pharmaceutics, complementing external beam radiotherapy, which primarily treats localized, radiographically defined lesions. By coupling diagnostic imaging with therapy, in a "radiotheranostic" paradigm, radiopharmaceutical therapy supports patient-specific target selection, dosimetry, and on-treatment monitoring. Progress in target discovery, radioligand chemistry, and optimization of pharmacokinetics and biodistribution has improved efficacy and safety, culminating in US Food and Drug Administration approvals of [177Lu]Lu-PSMA-617 (Pluvicto) for metastatic castration-resistant prostate cancer and [177Lu]Lu-DOTA-TATE (Lutathera) for neuroendocrine tumors. These successes highlight radiopharmaceutical therapy's expanding role across oncology. This review summarizes the evolution of radiopharmaceutical therapy from early clinical milestones to modern regulatory approvals, then surveys emerging radioligands directed at new molecular pathways. We also discuss strategies to enhance therapeutic response including rational combinations with DNA damage response agents such as poly(adenosine diphosphate-ribose) polymerase inhibitors or immunotherapies. Finally, we outline key challenges such as optimal patient selection, dosimetry standardization, therapeutic resistance, and access and highlight a few ways to accelerate broader clinical integration and continued innovation.