A collaborative effort between scientists from the Chinese Academy of Sciences has shed light on a pivotal mechanism that enhances the effectiveness and safety of bacterial cancer therapy. Led by Professor Liu Chenli and Professor Xiao Yichuan, this research introduces an engineered bacterial strain that targets tumor tissues while avoiding normal tissues, significantly improving therapeutic outcomes. The study, published in Cell, reveals how tissue-resident memory CD8+ T cells play a crucial role in antitumor responses through the modulation of interleukin-10 receptor (IL-10R) expression. This discovery opens new avenues for immuno-oncology and synthetic biology.

The exploration of bacteria as a tool in cancer treatment has roots dating back to the 19th century. However, translating this concept into clinical practice has been fraught with challenges, particularly concerning safety and efficacy. Recent advancements in synthetic biology have paved the way for the development of novel antitumor bacteria, yet their practical application remained limited due to unclear mechanisms of action. In response, researchers designed a genetically modified bacterial strain, referred to as Designer Bacteria 1 (DB1), which demonstrates remarkable tumor-targeting and tumor-clearing capabilities.

Researchers observed that DB1's ability to thrive within tumor tissues while being eliminated in healthy tissues is linked to its interaction with tissue-resident memory CD8+ T cells. These cells are reinvigorated and expanded following DB1 therapy, leading to enhanced antitumor responses. A key player in this process is interleukin-10 (IL-10), which binds to the IL-10 receptor (IL-10R) on CD8+ T cells, activating the STAT3 protein and promoting further IL-10R expression. This creates a positive feedback loop, enabling cells to "memorize" previous IL-10 stimulation during tumorigenesis, thereby enhancing their effectiveness against tumors.

To delve deeper into the molecular underpinnings of high IL-10R expression on CD8+ T cells, researchers conducted extensive computational and quantitative experiments. They discovered that IL-10 binding to IL-10R activates the STAT3 protein, which in turn promotes IL-10R expression. This positive feedback loop allows cells to bind more IL-10, creating a nonlinear hysteretic effect where CD8+ T cells retain memories of prior IL-10 exposure. This mechanism was exploited by the surge in IL-10 induced by DB1, which activated and expanded CD8+ T cells to eliminate tumor cells.

Further investigation revealed 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. This process underscores the critical role of IL-10R hysteresis in tumor-associated immune cells, highlighting its importance in bacterial cancer therapy.

This groundbreaking research not only elucidates a previously unresolved mechanism but also provides valuable insights for designing engineered bacteria that enhance both safety and efficacy. The findings offer a guiding principle for future developments in immuno-oncology, opening new horizons in the fight against cancer. The work represents a significant step forward in understanding how bacterial therapies can be optimized to target and eliminate tumors effectively.