Scientists have developed a groundbreaking approach to colorectal cancer treatment using genetically engineered Salmonella bacteria that self-destruct inside tumors to unleash powerful immune responses. The research, conducted by teams from the National University of Singapore's Yong Loo Lin School of Medicine (NUS Medicine) and Central South University in China, demonstrates significant promise for addressing one of the world's deadliest cancers.
Colorectal cancer ranks as the second leading cause of cancer-related mortality globally, accounting for more than 9% of all cancer deaths. Current immunotherapies often prove ineffective against this malignancy, creating an urgent need for innovative treatment strategies.
Novel Bacterial Engineering Approach
The research team modified a weakened strain of Salmonella typhimurium, which has previously shown safety in human trials for other cancers. The bacteria naturally target tumors, but the scientists enhanced this capability by incorporating a synchronized lysis circuit (SLC) that causes the bacteria to self-destruct in unison once they reach high density inside tumors.
Upon destruction, the engineered bacteria release a protein called LIGHT, which binds to the HVEM receptor on immune cells, triggering robust immune activation. "This work provides compelling evidence that mTLSs can be therapeutically induced using synthetic biotics," said co-corresponding author Xiaoyuan (Shawn) Chen, PhD, Professor in Medicine and Technology and Director of the Nanomedicine Translational Research Program at NUS Medicine.
Immune System Reprogramming
The therapy's mechanism centers on activating the LIGHT-HVEM signaling pathway to stimulate group 3 innate lymphoid cells (ILC3s) and initiate T cell-mediated antitumor responses. Chen explained that "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."
A critical breakthrough involves the formation of mature tertiary lymphoid structures (mTLSs) within tumor sites. These structures function as immune coordination hubs, resembling lymph nodes and facilitating local activation and proliferation of T cells and innate lymphoid cells. The formation of mTLSs has been correlated with enhanced patient survival across various cancers, particularly colorectal cancer.
Preclinical Results
Testing in two colorectal cancer mouse models—a genetic model where mice naturally develop intestinal tumors and a chemical model where cancer was induced—yielded promising results. The researchers observed significant shifts in immune cell populations, with treatment reversing the harmful conversion of protective ILC3 cells into less helpful ILC1 cells that typically occurs during colorectal cancer development.
The engineered Salmonella therapy not only increased tertiary lymphoid structures but "upgraded" them to mature forms with organized B-cell and T-cell zones, indicating effective immune niches. CD8+ T cells showed enhanced activity, producing higher levels of interferon-gamma (IFN-γ) and granzyme B, both crucial for immune responses and cancer cell elimination.
Treatment resulted in significantly reduced tumor growth, improved survival, and complete tumor control in some mice. Importantly, the therapeutic benefits depended on LIGHT-HVEM signaling and ILC3s—in mice lacking HVEM or ILC3s, the therapy failed to mature tertiary lymphoid structures or reduce tumors.
Safety and Targeting Profile
The bacterial therapy demonstrated impressive safety and biocompatibility in laboratory models. No off-target bacterial accumulation was observed in non-tumor tissues or organs, highlighting its targeted mode of action. Additionally, the treatment contributed to restoring healthy gut microbiota balance, an important factor given the microbiome's role in modulating systemic immunity.
Clinical Translation Potential
"This approach could pave the way for programmable 'living medicines' that reshape the tumor environment from within," said Pengfei Rong, MD, PhD, the study's other corresponding author from the Third Xianguya Hospital, Central South University.
The therapy could potentially complement existing treatments like checkpoint inhibitors or cancer vaccines by making colorectal cancer tumors more "immune-visible." The same strategy might be adapted for other difficult-to-treat solid tumors by modifying the therapeutic cargo the bacteria deliver.
Study Limitations and Future Directions
The research acknowledges several limitations, including that effects were observed in mice, and human immune systems and gut bacteria may respond differently. The engineered bacteria release multiple factors upon destruction, making it challenging to isolate LIGHT-specific effects. The exact subtypes of innate lymphoid cells and downstream pathways require further clarification.
Any live bacterial therapy carries inherent risks of unintended infection, inflammation, or unpredictable interactions with patient microbiota. The research team is conducting comprehensive preclinical evaluations to validate safety and effectiveness in preparation for human clinical trials.
The study was published in Science Translational Medicine, marking a significant advancement in the convergence of synthetic biology and cancer immunotherapy that could revolutionize colorectal cancer treatment paradigms.
