Targeted Radionuclide Therapy: Current Landscape and Combination Approaches to Improve Oncology Outcomes.

Targeted radionuclide therapy (TRT) is an emerging modality in oncology that delivers internal radiation specifically to tumor sites. It typically consists of a particle-emitting radionuclide, a linking complex with a chelator for securely binding radionuclides to targeting molecules, and a binding moiety of targets expressed on tumor cells. Early clinical results have been promising, with several TRT agents approved for treating various cancers, including prostate cancer and gastroenteropancreatic neuroendocrine tumors, or their microenvironment. However, most patients eventually relapse following TRT monotherapy, leaving room to further improve patient outcomes. Combination strategies could be beneficial to improve therapeutic index, enhance cytotoxic effects, or modulate tumor target expression; promising preclinical data have led to early-phase clinical trials. This review provides a concise overview of physical and chemical properties of commonly used β- and α-emitting radionuclides and a forward-looking rationale for combination regimens of TRT and other therapeutic modalities, such as hormone therapy, DNA damage repair inhibitors, immunotherapy, chemotherapy, external beam radiotherapy, and other combinations. We discuss the preclinical rationale, available clinical data, and ongoing key clinical trials with TRT combination therapy. Additionally, we highlight future perspectives including emerging radionuclides and prognostic and predictive biomarkers to optimize TRT combination therapy.