PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy.

Although chimeric antigen receptor (CAR)-T cells have demonstrated remarkable efficacy against hematologic malignancies, their effectiveness in solid tumors is limited by poor tumor infiltration and severe cytokine release syndrome (CRS). CAR-macrophage (CAR-M) therapy has emerged as a promising alternative, leveraging the innate tumor-homing capacity of macrophages while enabling antigen-specific phagocytosis and immune activation without triggering CRS. Prostate-specific membrane antigen (PSMA) represents an ideal therapeutic target due to its high expression in prostate cancer cells. In this study, we engineered PSMA-specific CAR-M with potent anti-tumor activity against prostate cancer cells both in vitro and in vivo. PSMA-specific CAR-M exhibited strong antigen-dependent phagocytic capability and underwent polarization toward a pro-inflammatory, tumoricidal phenotype upon PSMA recognition. Mechanistically, interaction with PSMA-expressing prostate cancer cells induced metabolic reprogramming, characterized by enhanced glycolytic activity and suppressed oxidative phosphorylation, which reinforced the anti-tumor function of CAR-M. Our findings highlight PSMA-targeted CAR-M therapy as a promising immunotherapeutic approach for prostate cancer.