Salmonella typhimurium engineered to secrete cytolysin A and hyaluronidase suppresses tumor growth and metastasis

Researchers engineered an attenuated Salmonella typhimurium strain (CNC018pCH) to secrete cytolysin A and hyaluronidase; in mouse tumor models this modified bacterium reduced tumor growth and metastasis and generated protective memory responses.

Researchers report an engineered Salmonella typhimurium strain designed to improve cancer therapy in mice. The base strain, CNC018, is highly attenuated but retains tumor-targeting specificity. The modified strain, CNC018pCH, uses a doxycycline-inducible system to secrete cytolysin A (ClyA) and hyaluronidase (HysA). The study evaluated effects on tumor growth, metastasis, and immune responses in multiple murine tumor models. Key findings: - The parent strain CNC018 is attenuated by 10^5–10^6-fold compared with wild-type but maintains tumor-targeting specificity. - CNC018pCH was engineered to secrete ClyA, a pore-forming toxin, and HysA, an enzyme that degrades hyaluronic acid, under doxycycline control. - Local ClyA secretion induced tumor cell death through pyroptosis, apoptosis, and necrosis (described as PANoptosis) in a cholesterol-dependent manner, releasing cellular contents and danger signals that can activate immune responses. - HysA degraded hyaluronic acid in the tumor microenvironment, promoted bacterial penetration into tumors, and was reported to inhibit metastasis via down-regulation of the ribosomal S6 kinase (RSK)-related signaling pathway. - In several mouse tumor models, CNC018pCH improved control of tumor growth and metastasis and produced memory responses that protected cured mice from tumor rechallenge. Summary: The engineered S. typhimurium strain combined a tumor-targeting attenuated bacterium with two therapeutic payloads that induced tumor cell death and remodeled the tumor microenvironment, and this combination was reported to reduce tumor growth and metastasis in mice while generating protective memory. Undetermined at this time.