Two types of bacteria work in "perfect harmony" to selectively attack cancer cells — Japan Advanced Institute of Science and Technology

Professor Eijiro Miyako's research group from the Materials Chemistry Frontiers Research Area, Japan Advanced Institute of Science and Technology (JAIST), in collaboration with Daiichi Sankyo and Professor Naoki Takaya from the Faculty of Life and Environmental Sciences at the University of Tsukuba, has successfully developed a new bacterial therapy called "AUN" where two types of bacteria work together with exquisite coordination, in "perfect harmony," to selectively attack cancer cells. In immunodeficient mice transplanted with human cancers (sarcoma, metastatic lung cancer, drug-resistant TNBC, etc.), they confirmed 100% efficacy, 100% survival for 120 days, and safety. Miyako stated, "We want to establish a startup in the United States by 2028 and begin Phase 1 trials within 6 years." The research was published in Nature Biomedical Engineering.

Bacterial therapy is not well-known in Japan, but research is steadily progressing in Europe and the United States. The use of anaerobic bacteria means they can accumulate easily in cancer cells that are in hypoxic conditions. However, conventional anaerobic bacteria have low therapeutic efficacy, so genetically modified bacteria such as Salmonella, Listeria, and E. coli are used, raising safety concerns.

AUN uses two natural bacteria: Proteus mirabilis [A-gyo] that is resident in tumors, and the photosynthetic bacterium Rhodopseudomonas palustris [UN-gyo] that exists in rivers and other environments. The research group had previously worked on developing photo-diagnosis and treatment technology for cancer using purple non-sulfur bacteria. During that process, they discovered that when purple non-sulfur bacteria were administered to cancerous mice, the tumor surface emitted light, and when near-infrared rays were applied, the cancer cells were attacked.

During that research, they discovered that combining A-gyo and UN-gyo resulted in strong aggressiveness against tumors, and in 2023, they announced high efficacy against mouse cancer.

However, it was unknown whether the treatment would be effective against cancers other than those derived from mice, particularly since human-derived cancers can only engraft and proliferate in immunodeficient animals. It was unclear whether the treatment would show effects even in immunodeficient environments.

When AUN was administered to localized pancreatic cancer model mice transplanted with human pancreatic cancer, the cancer was eliminated by day 6 after administration. Furthermore, even in ultra-immunodeficient humanized mice with broadly knocked-out immune systems transplanted with human colorectal cancer, the cancer tissue was eliminated by day 5.

The mechanism is extremely unique. When A-gyo and UN-gyo coexist in a 3:97 ratio, they are stable, but when they accumulate around cancer cells, only A-gyo enters the cancer cells. A-gyo repeatedly proliferates inside the cancer cells, reaching about 20% after 6 hours, and secretes cytolysins including toxins, hemolysin, phospholipase, and adenylyl cyclase, causing selective collapse of cancer cells. In fact, tumor discoloration and collapse of intratumoral blood vessels were observed. At that time, A-gyo was transformed by cancer metabolites and took on a spear-like shape, gaining motility and was observed repeatedly piercing cancer cells.

Genetic analysis of A-gyo revealed that genes related to pathogenic factors such as adhesin and pili were defective. Both A-gyo and UN-gyo are biosafety level 1 with no pathogenicity and can be easily removed with antibiotics.

Miyako commented: "Previous cancer immunotherapies required the presence of autoimmunity. AUN dynamically and physically attacks and removes cancer cells, so it can demonstrate high efficacy even in immunodeficient conditions. A-gyo and UN-gyo achieve high efficacy through co-cultivation, which can truly be said to be like perfect harmony. In clinical trials in the United States, we think patients who have had no effect with conventional treatments will be the target, but we want to expand the scope of application by producing results."

Journal Information
Publication: Nature Biomedical Engineering
Title: Tumour-resident oncolytic bacteria trigger potent anticancer effects through selective intratumoural thrombosis and necrosis
DOI: 10.1038/s41551-025-01459-9