Dual-targeting theranostic strategies to overcome receptor heterogeneity in neuroendocrine prostate cancer.

Prostate cancer (PC) is a highly heterogeneous malignancy characterized by dynamic alterations in surface biomarker expression during disease progression. Although prostate-specific membrane antigen (PSMA) remains the most clinically established target for PC imaging and therapy, receptor heterogeneity remains a major obstacle in advanced, treatment-resistant, and neuroendocrine prostate cancer (NEPC). These limitations have driven increasing interest in dual-targeting strategies to improve tumor coverage and therapeutic precision. Neurotensin receptor 1 (NTSR1) is predominantly expressed in aggressive androgen-independent and neuroendocrine tumors, whereas gastrin-releasing peptide receptor (GRPR) is highly expressed in early-stage and low-Gleason-score prostate cancer. The complementary expression profiles of PSMA, GRPR, and NTSR1 provide a strong rationale for developing dual-targeted theranostic platforms capable of overcoming tumor heterogeneity and lineage plasticity of advanced PC. This review discusses the biological significance, signaling pathways, expression dynamics, and recent advances in dual-targeting strategies for imaging and therapy of advanced PC.