(DAMPs), activating the cGAS- STING pathway, which induces type I interferons and the release of cytokines that recruit immune cells. 11,12 The growing promise of RPT in treating metastatic cancer, coupled with emerging insights into the immunogenic effects of radiation, has spurred preclinical and clinical studies exploring the combination of RPT and immunotherapy, such as ICIs. This review explores clinical trials investigating the combination of RPT with ICI, highlighting key clinical findings, potential challenges, and future directions in this emerging field. Radiopharmaceutical Therapy RPT has emerged as a promising systemic therapy, enabling radiation delivery to both local and metastatic lesions while sparing healthy tissues (Figure 1A). 8,13 Unlike EBRT, which delivers radiation to all tissues in the radiation field, including malignant and adjacent normal tissues, RPT uses tumor-targeting biomolecules (eg, antibodies, peptides, or small molecules) linked to a radionuclide to form a “radiopharmaceutical” that preferentially targets cancer cells (Figure 1). The radiopharmaceutical binds selectively to receptors overexpressed on tumor cells, thus delivering radiation to the tumor while minimizing damage to surrounding tissues. 14 This molecularly targeted approach makes RPT particularly effective for treating metastatic and microscopic tumors, 8,15-17 where EBRT’s utility is oſten limited. The efficacy of RPT depends on the targeting molecule’s properties, the radionuclide’s physical characteristics, and tumor characteristics such as receptor expression, size, and tumor type. Additional factors, such as the administrated activity, tumor uptake, and pharmacokinetics, also impact the treatment outcome. 18 Therefore, carefully considering these factors is crucial for RPT’s clinical efficacy and safety. The approvals of several radiopharmaceuticals, such as [ 223 Ra]Ra-dichloride (Xofigo) and [ 177 Lu]Lu-PSMA-167 (Pluvicto) for metastatic castration-resistant prostate cancer (mCRPC) and [ 177 Lu]Lu-DOTATATE (Lutathera) for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), have sparked a new excitement in the field. 19-21 RPT faces challenges like suboptimal targeting, radioresistance, and limited immune stimulation, hindering tumor eradication. 22-24 Combining RPT with systemic therapies like ICIs may overcome these limitations and improve outcomes. Targeting Molecules In RPT, antibodies, peptides, or small molecules are designed to bind selectively to tumor-specific receptors or antigens, ensuring precise delivery of radiation to cancer cells while sparing healthy tissues. 25 Antibodies Their high specificity and potentially strong binding affinity make antibodies ideal for targeting tumor-associated antigens and delivering radiation to cancer cells. 26,27 Effective antibodies target antigens that are highly expressed on tumors but minimally expressed or absent in healthy tissue. Figure 1. Radiopharmaceutical therapy delivers systemic radiation to tumor. (A) A radiolabeled, tumor-specific compound known as a “radiopharmaceutical” is administered intravenously, resulting in selective accumulation of radionuclide in the tumor microenvironment. (B) Pharmacophoric model of radiopharmaceutical agent. A targeting molecule is conjugated to a therapeutic radionuclide via a linker and chelator, forming a radiopharmaceutical that ensures precise delivery of radiation to tumor cells. A B Combination of Radiopharmaceutical Therapy and Immune Checkpoint Inhibitors March 2025 Applied Radiation Oncology 7