Radiopharmaceuticals and theranostics: reshaping cancer diagnosis and therapy with targeted radionuclides

The theranostic paradigm, combining molecular diagnosis and targeted radionuclide therapy in a single platform, has revolutionized precision oncology. Radiopharmaceutical theranostics enables targeted visualization, characterization, and treatment of malignancies through tumor-associated molecular targets, including prostate-specific membrane antigen (PSMA), somatostatin receptors (SSTR), and fibroblast activation protein (FAP). The approvals of ¹⁷⁷Lu-DOTATATE (Lutathera®) for GEP-NETs and ¹⁷⁷Lu-PSMA-617 (Pluvicto®) for mCRPC are groundbreaking advances that have triggered exponential growth in the field: the VISION study showed a 38% reduction in the risk of death with ¹⁷⁷Lu-PSMA-617, and NETTER-1 a 79% reduction in the risk of progression with ¹⁷⁷Lu-DOTATATE in midgut NETs. Beyond beta emitters, targeted alpha therapy (TAT) with actinium-225, radium-223, and lead-212 is emerging as a powerful strategy to overcome beta-particle resistance, as the high linear energy transfer of alpha particles delivers greater cytotoxicity even in radioresistant tumors. Novel targets such as FAP, CXCR4, HER2, and gastrin-releasing peptide receptor (GRPR) are further diversifying the theranostic armamentarium across malignancies. This review synthesizes the current status of the field, spanning the radiobiology of targeted radionuclide therapy, clinical evidence from pivotal and ongoing trials, alpha-emitting radioisotopes, next-generation radioligands, the growing role of AI-enabled personalized dosimetry, and combination therapies with immunotherapy, PARP inhibitors, and androgen-receptor pathway inhibitors. We also address current challenges heterogeneous target expression, dose-limiting toxicities, radionuclide supply-chain constraints, and the regulatory framework as well as future directions poised to expand the theranostic paradigm to a broader range of cancers.