Combining PSMA-Targeted Radiopharmaceutical Therapy with Immunotherapy

PSMA-targeted radiopharmaceutical therapy (RPT) is a standard treatment for metastatic castration-resistant prostate cancer (PCa), exploiting PSMA overexpression to deliver cytotoxic radiation. Treatment with the β-emitter [¹⁷⁷Lu]Lu-PSMA-617, approved in 2022, has been associated with prolonged progression-free and overall survival in patients with PCa. However, resistance and heterogeneous patient responses limit its efficacy. Although immunotherapy is effective in several malignancies, PCa’s immunosuppressive microenvironment often reduces its impact. Combining targeted RPT with immune checkpoint inhibitors, particularly programmed cell death protein 1 and programmed cell death ligand 1 inhibitors, may enhance antitumor responses. This review explores the rationale behind this combination, evaluates preclinical and clinical evidence, and discusses future directions for integrating immune checkpoint blockade with targeted RPT.