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Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer death globally.

The numbers tell the story:

Worldwide 2022:

  • 1,926,118 new colorectal cancer cases
  • 903,859 deaths

However, traditional treatment methods for colorectal cancer have certain limitations...

Surgery

Surgery

Chemotherapy

Chemotherapy

Radiotherapy

Radiotherapy

To achieve more precise and effective treatment for colorectal cancer

we engineered

bacterial warriors

What is engineered bacterial therapy?

Engineered bacterial therapy is an emerging treatment method. Its core concept is to utilize genetic engineering and other technologies to modify natural bacteria, enabling them to acquire new functions that can be used for disease diagnosis, prevention or treatment. Then, these "modified" bacteria are used as living drugs to treat diseases.
Illustration of engineered bacteria

The difficulties

The immunosuppressive tumor microenvironment (TME) of colorectal cancer is characterized by tumor-associated macrophages (TAMs) dominating as the tumor-promoting M2 phenotype to suppress immunity and fuel tumor growth. TME acts like an impenetrable fortress, suppressing immune responses and promoting tumor progression.
Tumor microenvironment illustration

Our solution

MAGIC

Macrophage-Activated c-di-GMP Immunotherapy for Colorectal Cancer

Trojan Horse strategy illustration

"Trojan Horse" strategy

We designed a "Trojan Horse" strategy, sneaking into the "fortress" to reactivate the immune system from within, and transform immunosuppressive tumors into immunoreactive ones.

The "Horse" —— Escherichia coli Nissle 1917 (EcN)

The carrier that sneaks into the tumor via its natural ability to colonize hypoxic TME regions.

Advantages of EcN:

  • •Safety: EcN is a safe probiotic with few adverse reactions.
  • •Tumor targeting: EcN naturally colonizes hypoxic tumor areas in TME.
  • •Delivery capability: EcN produces, stores, and releases c-di-GMP as needed.
EcN bacteria illustration

The "Soldiers" —— c-di-GMP production system

A hypoxic-response plasmid generates the immune-activating molecule cyclic diguanylate monophosphate (c-di-GMP).

c-di-GMP production system

As a bacterial second messenger, c-di-GMP has two key roles:

1. Biofilm Barrier Construction

c-di-GMP inhibits the motility of engineered bacteria and enables them to form a biofilm, localizing the bacteria to the tumor site.

Biofilm formation

2. Tumor Immune Microenvironment Regulation

After being phagocytosed by TAMs, engineered bacteria release c-di-GMP to act on the STING pathway. This alters the polarization state of TAMs, reversing the M2 phenotype to the tumor-fighting M1 phenotype and activating anti-tumor immune responses.

Immune regulation
Suicide system illustration

The "Commander" —— Suicide system

EcN is triggered to release c-di-GMP at the right time via an inducer Acyl-Homoserine Lactone (AHL).

A "suicide" safety plasmid controls therapeutic release through the exogenous administration of AHL. AHL-induced activation of phospholipase A (PhlA) causes rapid bacterial lysis, enabling release of c-di-GMP into the TME.

Macrophage attack illustration

The reprogrammed macrophages then launch a direct attack, killing tumor cells and restoring immune activity.

Oral capsule delivery

Delivery approach

To translate our bacterial immunotherapy strategy into practical colorectal cancer treatment, we plan to deliver the engineered EcN via oral capsules—a non-invasive, patient-friendly approach.

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