Targeted Delivery of Indole-3-Pyruvic Acid Suppresses Macrophage Ferroptosis to Enhance CD8+ T Cell-Mediated Immunotherapy Response in Bladder Cancer.

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.