Chiral Cascade-Targeted Nanoassembly Eradicates Intratumoral Bacteria via Ferroptosis to Potentiate STING-Driven Antitumor Immunity

Intratumoral bacteria, particularly those residing intracellularly, are emerging as critical regulators of tumor progression and immunosuppression, yet their precise eradication and conversion of this process into an immunostimulatory signal remain a formidable challenge. Here, we report a chiral supramolecular nanoassembly, ZnO 2 @CDP/Fc-DA, designed for cascade targeting of tumor cells and intracellular bacteria via d -alanine-mediated chiral matching and metabolic labeling. This system acts as a “Trojan horse”, disassembling in the acidic lysosomes of tumor cells to release H 2 O 2 and ferrocene-derivatized d -alanine (Fc-DA). The sustained Fenton reaction induces bacterial ferroptosis, an immunogenic form of bacterial death, which triggers the release of microbial DNA. This bacterial DNA, synergizing with the concurrently released Zn 2+, robustly activates the cGAS-STING pathway, a cornerstone of innate immunity. Concurrently, the nanoassembly promotes immunogenic cell death (ICD) in tumor cells via ROS-mediated ferroptosis. The synergistic engagement of bacterial DNA-driven STING activation and tumor cell ICD reprograms the immunosuppressive tumor microenvironment, leading to dendritic cell maturation, cytotoxic T-cell infiltration, and profound inhibition of both primary and metastatic tumors. In contrast, the l -enantiomeric control (ZnO 2 @CDP/Fc-LA) showed an inferior efficacy. This work presents a chirality-guided strategy that harnesses intratumoral bacteria as an endogenous trigger for potent antitumor immunity, establishing bacterial ferroptosis as a powerful modality for microbiome-potentiated immunotherapy.