Targeting Peptostreptococcus anaerobius with an Iron‐Based Nanozyme Reverses Ferroptosis Resistance and Enhances Antitumor Immunity in Colorectal Cancer

An iron‐based nanozyme selectively eliminates intratumoral P. anaerobius while catalytically generating ROS to induce ferroptosis, synergistically suppressing colorectal cancer growth and activating anti‐tumor immunity through immunogenic cell death. ABSTRACT The intratumoral microbiota is a critical determinant of therapeutic outcomes in colorectal cancer (CRC). Although several microbial species have been identified that influence CRC development and treatment resistance, effective strategies for precisely modulating these bacteria remain limited. In this study, we identify Peptostreptococcus anaerobius as a tumor‐enriched anaerobe that promotes CRC progression by inhibiting ferroptosis. To counteract this, we engineered a composite iron‐based nanozyme encapsulating lincomycin, which selectively targets and eradicates intratumoral P. anaerobius, thereby reversing ferroptosis resistance in CRC. Simultaneously, the nanozyme's inherent peroxidase (POD) like activity catalyzes hydroxyl radical generation, enhancing intracellular oxidative stress and promoting ferroptosis. This dual mechanism‐microbial clearance and ROS‐mediated ferroptosis induction‐synergistically suppresses tumor growth. Moreover, ferroptotic cancer cells release large amounts of damage‐associated molecular patterns (DAMPs), which trigger immunogenic cell death (ICD), promoting dendritic cell (DC) maturation and T cell activation, thereby enhancing anti‐tumor immunity. Our findings highlight a novel ferroptosis‐centered therapeutic strategy integrating microbiota modulation and catalytic nanomedicine for precise CRC treatment. An iron-based nanozyme selectively eliminates intratumoral P. anaerobius while catalytically generating ROS to induce ferroptosis, synergistically suppressing colorectal cancer growth and activating anti-tumor immunity through immunogenic cell death. ABSTRACT The intratumoral microbiota is a critical determinant of therapeutic outcomes in colorectal cancer (CRC). Although several microbial species have been identified that influence CRC development and treatment resistance, effective strategies for precisely modulating these bacteria remain limited. In this study, we identify Peptostreptococcus anaerobius as a tumor-enriched anaerobe that promotes CRC progression by inhibiting ferroptosis. To counteract this, we engineered a composite iron-based nanozyme encapsulating lincomycin, which selectively targets and eradicates intratumoral P. anaerobius, thereby reversing ferroptosis resistance in CRC. Simultaneously, the nanozyme's inherent peroxidase (POD) like activity catalyzes hydroxyl radical generation, enhancing intracellular oxidative stress and promoting ferroptosis. This dual mechanism-microbial clearance and ROS-mediated ferroptosis induction-synergistically suppresses tumor growth. Moreover, ferroptotic cancer cells release large amounts of damage-associated molecular patterns (DAMPs), which trigger immunogenic cell death (ICD), promoting dendritic cell (DC) maturation and T cell activation, thereby enhancing anti-tumor immunity. Our findings highlight a novel ferroptosis-centered therapeutic strategy integrating microbiota modulation and catalytic nanomedicine for precise CRC treatment. Advanced Science, EarlyView.