177Lu-PSMA-617 radioligand therapy as an immune modulator in prostate cancer.

INTRODUCTION

Metastatic castration-resistant prostate cancer (mCRPC) remains a therapeutic challenge despite advances in systemic treatments. Prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with 177Lu-PSMA-617 has emerged as an effective strategy, and increasing evidence suggests that its activity may extend beyond direct cytotoxicity to the modulation of the tumor immune microenvironment.

AREAS COVERED: A narrative literature review was conducted using the PubMed database to identify relevant studies published up to January 2026. This review summarizes preclinical and clinical evidence on the immunomodulatory effects of PSMA-targeted RLT. We discuss how 177Lu-PSMA-617 influences immune cell populations, induces immunogenic cell death, and interacts with key microenvironmental factors such as hypoxia, vascularization, and PSMA heterogeneity. The role of alternative radioligands, including alpha-emitters and fibroblast activation protein-targeted agents, is also examined.

EXPERT OPINION: PSMA-targeted RLT represents a promising immune-priming modality in mCRPC, but its clinical impact is limited by tumor and microenvironmental heterogeneity. Biomarker-driven patient selection, optimized dosimetry, and rational combination strategies with immunotherapy will be essential to fully exploit its immunomodulatory potential and to achieve durable clinical benefit.