For decades, scientists have explored the potential of bacteria in fighting cancer, but safety and efficacy barriers have stood in the way. Now, a research team has cracked the code behind how genetically engineered bacteria, specifically DB1, can selectively target and eliminate tumors.

A team of researchers, led by Prof. Chenli Liu from the Shenzhen Institutes of Advanced Technology at the Chinese Academy of Sciences (CAS) and Prof. Yichuan Xiao from the Shanghai Institute of Nutrition and Health at CAS, has uncovered the key mechanism behind bacterial cancer therapy using a genetically engineered bacterial strain. Their findings were published today (March 3) in the scientific journal Cell.

The idea of using bacteria to fight cancer dates back to the 1860s. However, despite its long history, bacterial-based cancer therapy has struggled to gain clinical traction due to concerns about safety and effectiveness.

Challenges and Innovations in Synthetic Biology

Recent advancements in synthetic biology have led to the creation of novel antitumor bacteria, opening new possibilities in immuno-oncology. Yet, one major challenge has remained: understanding how these bacteria evade the body’s immune system while simultaneously activating an antitumor response.

In this study, researchers developed an engineered bacterial strain called Designer Bacteria 1 (DB1). This strain is designed to thrive in tumor tissue while being eliminated from healthy tissue, achieving both a highly targeted approach to tumors and an effective tumor-clearing effect.

Unraveling the Role of CD8+ TRM Cells

To understand how DB1 simultaneously achieves these effects, researchers investigated the interactions between the bacteria and tumors. They discovered that DB1’s antitumor efficacy is closely linked to tissue-resident memory (TRM) CD8⁺ T cells within the tumor, which are reinvigorated and expanded following DB1 therapy. Interleukin-10 (IL-10) plays a crucial role in mediating this effect, with efficacy depending on the high expression of interleukin-10 receptor (IL-10R) on CD8⁺ TRM cells.

The IL-10 Feedback Loop and Tumor Memory

To investigate the molecular mechanisms underlying the high expression of IL-10R on CD⁸⁺ TRM cells, researchers conducted a series of computational and quantitative experiments. They found that IL-10 binds to IL-10R on CD⁸⁺ TRM cells, activating the STAT3 protein and further promoting IL-10R expression. This established a positive feedback loop, enabling cells to bind more IL-10 and creating a nonlinear hysteretic effect, whereby CD⁸⁺ TRM cells “memorize” previous IL-10 stimulation during tumorigenesis. The high expression of IL-10R on CD⁸⁺ TRM cells was exploited by a bacteria-induced IL-10 surge, which activated and expanded CD⁸⁺ TRM cells to clear tumor cells.

Tumor Microenvironment and Immune System Modulation

To examine the source of IL-10 within the tumor microenvironment (TME) after bacterial therapy, researchers found that tumor-associated macrophages (TAMs) upregulate IL-10 expression following DB1 stimulation via the Toll-like Receptor 4 (TLR4) signaling pathway. Interestingly, IL-10 reduced the migration speed of tumor-associated neutrophils (TANs), aiding DB1 in evading rapid clearance. These processes depended on high IL-10R expression in tumor-associated immune cells, highlighting the critical role of IL-10R hysteresis.

A New Path for Bacterial Cancer Therapy

“Our findings illuminate a crucial, yet previously unresolved mechanism in bacterial cancer therapy. The elucidated IL-10R hysteresis mechanism not only provides valuable insights but also serves as a guiding principle for the design of engineered bacteria, enhancing safety and efficacy,” said Prof. Liu.

Reference: “Bacterial immunotherapy leveraging IL-10R hysteresis for both phagocytosis evasion and tumor immunity revitalization” 3 March 2025, Cell.