Targeted Delivery of Indole‐3‐Pyruvic Acid Suppresses Macrophage Ferroptosis to Enhance CD8 + T Cell‐Mediated Immunotherapy Response in Bladder Cancer
Jianwen Lao, Xinhao Yuan, Shuai Liang, Kai Deng, Daqin Wu, Longhao Xu, Kun Zheng, Yi Lin, Peicong Cai, Haoran Zheng, Junyu Chen, Mingli Luo, Yan Chen, Xiong Chen, Chunhui Wang, Wenlong ZhongABSTRACT
Intratumoral microbiota‐related metabolites are emerging regulators of tumor immunity, yet their therapeutic potential remains largely unexplored. Here, indole‐3‐pyruvic acid (I3P), a Lactobacillus‐associated tryptophan metabolite, is identified as a molecule associated with immunotherapy response in bladder cancer. Mechanistically, I3P suppresses macrophages ferroptosis and sustains CD8 + T cell activity through an AHR–NF‐κB–SLC7A11 signaling axis that maintains macrophages redox homeostasis. Disruption of AHR or NF‐κB signaling abolishes these effects. Notably, liposomal delivery of I3P facilitates efficient targeting of tumor‐associated macrophages and enhances immunotherapy response without apparent toxicity. Together, these findings identify I3P as an immunoregulatory metabolite that potentiates anti‐tumor immunity and support nanoparticle‐mediated delivery as a promising strategy for immunotherapy sensitization in bladder cancer.