Clostridium ablates tumors by degrading collagen mesh and inducing ferroptosis

Abstract The supportive role of extracellular matrix in tumor growth and the drug resistance of tumor cells stand the major challenges in treating cancer. Here, we report the discovery of an oncolytic Clostridium strain, named RJ-1, which simultaneously expresses collagenases and produces iron-containing particles through intrabacterial mineralization. The secreted collagenases degrade pre-existing collagen mesh and show a collagen concentration-dependent degradation feature. Iron-containing particles released from RJ-1 by autolysis generate ferrous ions in the lysosomal acid environment following cell uptake and subsequently induce ferroptosis via the Fenton reaction. Due to selective germination in tumor sites, systemic administration of RJ-1 spores synchronously destructs dense tumor extracellular matrix and causes non-apoptotic tumor cell death. In collagen-dense tumor-bearing mice, a single intravenous injection achieves a favorable tolerance and rapid oncolysis of giant tumors with a size of ∼1000 mm 3 . This work finds a dual collagenase-expressing and iron-concentrating bacterium, proposing an alternative strategy to combat tumors.