Prostate-specific membrane antigen in malignant brain tumors: vascular heterogeneity, imaging promise, and therapeutic challenges

Abstract

Malignant brain tumors have high morbidity and poor prognosis. Prostate-specific membrane antigen (PSMA) has emerged as a promising vascular biomarker in this setting, particularly in gliomas and brain metastases. This review synthesizes current evidence on PSMA expression patterns, regulatory mechanisms, imaging applications, and translational potential in malignant brain tumors. Across studies, PSMA expression in gliomas is predominantly localized to tumor-associated neovasculature and closely associated with angiogenic signaling. In brain metastases, PSMA expression appears more heterogeneous and more strongly influenced by metastatic origin and the brain microenvironment. These biological features provide a rationale for PSMA-targeted positron emission tomography, which offers high lesion-to-background contrast. Clinically, PSMA-targeted imaging shows promise for glioma grading, selected post-treatment assessment, and detection of brain metastases across multiple primary tumors. However, therapeutic translation remains limited because compartment-specific target distribution, inconsistent target retention, delivery barriers, and uncertain dosimetry continue to constrain the efficacy of PSMA-targeted treatment strategies in malignant brain tumors. Current evidence supports PSMA as a promising complementary imaging biomarker rather than as a validated therapeutic target in malignant brain tumors. Future progress will require standardized detection methods, stronger mechanistic validation, and dosimetry-guided clinical development.