PSMA targeted Therapy: From molecular mechanisms to clinical breakthroughs in castration-resistant prostate cancer

Prostate cancer (PCa) is one of the most prevalent malignancies among men worldwide and remains the second leading cause of cancer-related mortality in this population. While androgen deprivation therapy (ADT) is initially effective, most patients eventually progress to castration-resistant prostate cancer (CRPC), a stage characterized by aggressive disease behavior and limited treatment options. Prostate-specific membrane antigen (PSMA) has emerged as a pivotal biomarker in PCa pathogenesis, with its overexpression in malignant cells providing a compelling target for both diagnostic imaging and therapeutic intervention.This review explores the multifaceted role of PSMA in tumor progression, highlighting its involvement in neoangiogenesis, metabolic reprogramming, and therapeutic vulnerabilities. We critically examine the latest advancements in PSMA-targeted treatment strategies, including radioligand therapy (e.g., ¹⁷⁷Lu-PSMA-617), antibody-drug conjugates, bispecific T-cell engagers, and small-molecule PSMA inhibitors. Clinical studies have demonstrated that PSMA-directed therapies can significantly reduce prostate-specific antigen (PSA) levels, improve radiographic progression-free survival (rPFS), and enhance patient-reported quality of life. However, challenges such as heterogeneous PSMA expression and acquired resistance necessitate further investigation. Ongoing clinical trials are actively exploring combinatory approaches, integrating PSMA-targeted therapy with radiotherapy, chemotherapy, and immunotherapy to optimize therapeutic efficacy. This review underscores the promise of PSMA-targeted strategies in advancing precision medicine for mCRPC, paving the way for improved survival outcomes and a better quality of life for affected patients.