PSMA-targeted CAR-macrophages drive glycolytic reprogramming for enhanced prostate cancer immunotherapy
Yangli Xu, Duoli Xie, Chunhao Cao, Zhuqian Wang, Yue Ju, Lili Guan, Xuelong Li, Shanshan Wu, Luo Zhang, Chao Liang, Xiushan Yin
Abstract
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.