Advances in molecular targets for oncologic radionuclide therapy

Abstract Oncologic radionuclide theranostics integrates molecular imaging with targeted radionuclide therapy through target-specific ligands, allowing a shared molecular target to guide patient selection, lesion characterization, treatment delivery, dosimetry, and response monitoring. This review provides a cross-target comparison of four representative systems—prostate-specific membrane antigen (PSMA), somatostatin receptor (SSTR), C-X-C chemokine receptor 4 (CXCR4), and fibroblast activation protein inhibitor (FAPI)—rather than considering each platform in isolation. PSMA- and SSTR-directed approaches have established clinically important theranostic pathways in prostate cancer and well-differentiated neuroendocrine tumors, respectively, supported by PET-based target visualization, standardized radioligand therapy, and an expanding clinical evidence base. By contrast, CXCR4-directed therapy is currently concentrated in selected hematologic malignancies and transplant-related settings, whereas FAPI-based approaches extend theranostics toward cancer-associated fibroblasts and stromal-rich solid tumors but remain at an earlier stage of therapeutic translation. Across these systems, differences in target biology, intrapatient heterogeneity, ligand pharmacokinetics, radionuclide selection, and normal-organ uptake determine clinical readiness and treatment feasibility. We summarize representative imaging and therapeutic agents, disease settings, evidence maturity, dosimetry, and organ-specific toxicities, and discuss how radionuclide therapy may be integrated with systemic therapy, hematopoietic stem-cell transplantation, supportive care, and multidisciplinary decision-making. Current evidence supports PSMA and SSTR as the most mature clinical models, while CXCR4 and FAPI require more prospective validation and standardized treatment pathways. Particular attention is given to toxicity management, treatment sequencing, and multimodal integrative oncology. Future progress will depend on individualized dosimetry, improved ligand retention and selectivity, protection of critical organs, rational combination and sequencing strategies, and patient-centered outcome assessment.