In a new study that combines synthetic biology with cancer immunotherapy, researchers from the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) and Central South University in China have developed an engineered strain of gut-homing bacteria that stimulates potent antitumor immune responses against colorectal cancer (CRC).
Antitumor immune responses refer to the actions taken by the body’s immune system to recognize, attack, and destroy cancer cells. It operates like the body’s internal surveillance system, spotting rogue cells (like tumor cells) and activating its defense forces to eliminate them.
Harnessing the immune system to fight cancer offers a powerful and precise approach to disease control. Unlike traditional treatments such as chemotherapy or radiation, which can harm healthy cells, immune responses can selectively target and destroy cancer cells with high specificity.
However, many tumors develop ways to suppress or evade the immune system, creating a hostile microenvironment that works to hide them from immune attack. Enhancing antitumor immune responses helps overcome this suppression and has been linked to improved treatment outcomes and longer survival rates.
There is currently an unmet need for better treatment options for patients with advanced CRC, which is the second leading cause of cancer death worldwide, sitting at over 9% of all cancer deaths. By engineering bacteria to target both tumors and trigger immune responses locally, the researchers hope to advance a new class of synbiotic therapies.
The research, published in Science Translational Medicine, demonstrates that a genetically modified Salmonella typhimurium strain can colonize tumors and release a therapeutic protein, LIGHT, to induce the formation of mature tertiary lymphoid structures (mTLSs) in laboratory models. These immune ‘hubs’ are associated with improved survival and stronger responses to treatment in CRC.
“This work provides compelling evidence that mTLSs can be therapeutically induced using synthetic biotics,” said Professor Shawn Chen Xiaoyuan, Nasrat Muzayyin Professor in Medicine and Technology from the Department of Diagnostic Radiology, and Director at the Nanomedicine Translational Research Programme (TRP) at NUS Medicine. “Our engineered strain stimulates a key immune signaling pathway, LIGHT-HVEM, to activate group 3 innate lymphoid cells and kickstart T cell–mediated antitumor responses.”
The bacterial therapy not only suppressed tumor growth and improved survival in the laboratory models, but also restored healthy gut microbiota and showed excellent biocompatibility. Importantly, the treatment was well tolerated in vivo, with no off-target accumulation in other organs.
“This approach could pave the way for programmable ‘living medicines’ that reshape the tumor environment from within,” added co-lead author Professor Pengfei Rong, Department of Radiology, The Third Xiangya Hospital, Central South University.
Next steps for the research team include rigorous testing and advancing toward human clinical trials to assess safety and efficacy in patients.
More information:
Ze Mi et al, Synthetic biology–driven induction of mature TLS formation enhances antitumor immunity in colorectal cancer, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.ado8395
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