3.3 Innovations in Non-Radiolabeled Targeted Therapy In addition to radiolabeled ligands, bispecific antibodies have made significant progress in PSMA-targeted therapy. Studies have shown that PSMAxCD3 bispecific antibodies can induce partial responses in 36% of chemotherapy-resistant patients, a mechanism involving the reprogramming of the tumor immune microenvironment (5, 28). Furthermore, novel PSMA-targeted therapeutic strategies such as antibody-drug conjugates (ADCs) and CAR-T cell therapy are at various stages of development, offering new options for patients who have failed multiple lines of treatment (5).
4 Challenges and Future Directions 4.1 Current Diagnostic and Therapeutic Bottlenecks Although significant advancements have been made in PSMA-targeted diagnostic and therapeutic techniques, three key challenges remain in clinical practice: 1. Salivary Gland Toxicity: The physiological accumulation of radiolabeled ligands in salivary glands leads to persistent xerostomia in approximately 35% of patients, significantly impacting quality of life. This is associated with high PSMA expression in salivary gland tissue, and current protective measures are largely ineffective (5, 29). 2. Heterogeneity of the Target: 15-20% of patients have low PSMA-expressing lesions, with about 30% exhibiting an "mismatch phenotype" characterized by FDG positivity and PSMA negativity, leading to suboptimal treatment outcomes (5, 26). Particularly, neuroendocrine-differentiated prostate cancer often shows absent PSMA expression (26). 3. Resistance Mechanisms: Secondary resistance is a major focus in PSMA-targeted therapy research, involving multiple mechanisms such as P-glycoprotein efflux, activation of DNA repair pathways (e.g., upregulation of ATM/ATR pathways), and loss of antigen epitopes (25, 26). Clinical studies have shown that approximately 40% of patients experience disease progression within 6 months of receiving [¹⁷⁷Lu]Lu-PSMA-617 treatment (25, 26).
