Research status and future direction of tumor bacterial immunotherapy

preface

In recent years, immunotherapy using drugs to reactivate or enhance immune surveillance has emerged as a new and promising cancer treatment strategy

Dating back to the origins of modern immunotherapy, bacteria have long been used as drugs

In recent years, studies have also demonstrated the presence of bacteria within tumors and the immunomodulatory role of the microbiota, suggesting that tumor tissue is a complex of bacteria interacting with tumor cells and hosts

Natural advantages of bacteria

Bacteria are tumor-targeted, and their surface structures or metabolites can also activate the immune system to exert anti-tumor effects

Tumor targeting of bacteria

The vasculature in tumor tissue is often chaotic and irregular, leading to insufficient

Immune activating properties of bacteria

Hypoxia, as a marker of TME, also leads to functional inhibition

For example, Salmonella LPS can increase the expression of IL-1β and exert antitumor effects through inflammatory bodies and Toll-like receptor 4 (TLR4)-mediated signaling pathways

In addition, certain components of bacteria can mediate the phenotypic transformation

Engineered bacteria

The chemogration of bacteria at the tumor site and its immunogenicity make it an ideal candidate for immunotherapy

Engineering improves tumor propensity

The construction of nutrient-deficient mutants is a strategy

In addition, synthetic engineered adhesins, specifically designed to bind specific cancer expression molecules, such as neoantigens or other molecules abundant in cancer cells, can enhance the natural affinity

Engineered regulation of the immune microenvironment

Several basic components of bacteria are able to alter the body's immune system

Given that bacteria preferentially colonize malignant areas and naturally stimulate innate immune cells, bacterial-based treatments can provide baseline levels

Human papillomavirus type 16 onclin E7 (HPV-16 E7) plays a key role in the pathogenesis of cervical cancer and is required for

Engineering improves safety

Although bacteria have good anti-tumor properties, their potential toxicity is a major obstacle

Bacterial surface molecules are the main virulence of bacteria, and modification of these surface antigens (such as gene knockout) is the main way to avoid the toxicity of live pathogens

Research status of engineered bacteria in tumor combination immunotherapy

Studies have shown that bacteria can act as immunotherapeutic agents to enhance anti-tumor immunity
.
Because combination therapy is a widely used strategy to improve overall efficacy, bacterial immunotherapy is also being used as part of
combination chemotherapy, radiotherapy, photodynamic therapy, and photothermal therapy.

Combination chemotherapy

The lack of specific delivery of malignant tissue by conventional chemotherapy results in significant systemic exposure to the drug, which often produces dose-limiting toxicity
.
The use of engineered bacteria as a drug release system for drug control release, as well as the use of their immunogenicity for immunomodulation, has become a hot spot
in research.

Ektate et al.
attached low-temperature sensitive liposomes to the Salmonella membrane and, with the help of high-intensity focused ultrasound (HIFU) heating, mediated the triggered release of intracellular doxorubicin in colon cancer cells, thereby enabling efficient drug delivery
in the cytoplasm and nuclei of cancer cells.
In addition, the strain polarized macrophages to the anti-tumor M1 phenotype, enriched the Th1 cell population with a large amount of TNF-α, and reduced the expression of IL-10, thus showing enhanced therapeutic effects
in combination chemotherapy-immunotherapy.

In addition to utilizing live bacteria, bacterial outer membrane vesicles (OMVs) are naturally produced by gram-negative bacterial membranes during growth and have recently become immunotherapeutic agents for a variety of biomedical applications
.
Chen et al.
encapsulate drug-carrying polymer micelles into bacterial outer membrane vesicles, where bacterial components activate the immune response, while drug-loading can act as chemotherapeutic and immunomodulatory to remove cancer cells
.

Combined radiation therapy

Bacterial-assisted radiation therapy is a new approach to
tumor treatment.
In a study by Jiang et al.
, the therapeutic effects of E.
coli in combination with radiation therapy were studied, showing that tumors in colon tumor models shrank
significantly in colon tumor models in the case of radiation of 21 Gy and escherichia producing cytohemolyticin a.
Combined radiation therapy with bacteria carrying cytohemolysin a can lead to more tumor remission
than bacterial therapy alone.

In addition, after radiation therapy, tumors release large amounts of tumor antigens that can be absorbed and presented by dendritic cells, leading to a specific adaptive immune response
.
However, in immunosuppressive TME, the number of DCs is usually low and they are often in a dysfunctional state
.
Wang et al.
injected Salmonella coated with antigen-adsorbed cationic polymer nanoparticles into tumor tissue, which capture antigens released after radiotherapy and transport them out of the tumor core, thereby activating dc
around the tumor margin tissue.
Studies have observed a significant increase in in vitro-activated DC, prolonged survival in multiple tumor mouse models, and shown enhanced systemic anti-tumor effects
.

Combined photodynamic therapy and photothermal therapy

Due to the non-specific killing effect and complex surgical procedures of standard tumor treatment, photodynamic therapy and photothermal therapy are new treatment options
because of their non-invasiveness, high specificity, and good spatiotemporal control.
Recently, many studies have attempted to utilize bacteria as vectors to load therapeutic agents for PDT and PTT to take advantage of the bacteria's tumor targeting and immunoactivation properties
.

One study integrated photosensitizer-coated nanoparticles onto the surface
of photosynthetic bacterial polycoccus.
Under the 660nm laser irradiation, photosynthetic bacteria continue to produce oxygen, ensuring the production of reactive oxygen species and enhancing the effect
of photodynamic therapy.
As an immunogenic bacterium, polycocci also activate local immunity
by upregulating the expression of MHC class II molecules and IL-12.
At the same time, this treatment induces immunogenic apoptosis by upregulating cell surface calretic reticullin and has shown good therapeutic effects
in a triple-negative breast cancer model.

brief summary

Since the first trial of BCG as a bladder cancer drug, there has been a relentless practice to study the role
of BCG in the treatment of cancers other than bladder cancer.
In addition to BCG, other bacterial preparations, such as the modified Salmonella typhimurium strain, are also in the preclinical or clinical trial phase to better validate their safety and therapeutic efficacy
.

Since bacteria are a complex and viable therapeutic agent, some uncontrollable mutations in their proliferation process may bring potential toxicity
.
Their inherent virulence can also lead to complex infections
in immunocompromised cancer patients.
However, the rapid development of synthetic biology makes it possible to obtain the desired bacterial behavior through gene editing, relying on the precise regulation of the targeting of engineered bacteria, the specific release of drugs at the tumor site can be achieved, and the future engineered bacteria will become a strong support for tumor immunotherapy, so that more cancer patients can benefit
.

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