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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Yangli Xu,
  • Duoli Xie,
  • Chunhao Cao,
  • Zhuqian Wang,
  • Yue Ju,
  • Lili Guan,
  • Xuelong Li,
  • Shanshan Wu,
  • Luo Zhang,
  • Chao Liang,
  • Xiushan Yin

摘要

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.