Recent Advances in Bacteria-Based Cancer Treatment

Abstract

Owing to its unique mechanism of abundant pathogen-associated molecular patterns in antitumor immune responses, bacteria-based cancer immunotherapy has recently attracted wide attention. Compared to traditional cancer treatments such as surgery, chemotherapy, radiotherapy, and phototherapy, bacteria-based cancer immunotherapy exhibits the versatile capabilities for suppressing cancer thanks to its preferentially accumulating and proliferating within tumors. In particular, bacteria have demonstrated their anticancer effect through the toxins, and other active components from the cell membrane, cell wall, and dormant spores. More importantly, the design of engineering bacteria with detoxification and specificity is essential for the efficacy of bacteria-based cancer therapeutics. Meanwhile, bacteria can deliver the cytokines, antibody, and other anticancer theranostic nanoparticles to tumor microenvironments by regulating the expression of the bacterial genes or chemical and physical loading. In this review, we illustrate that naïve bacteria and their components can serve as robust theranostic agents for cancer eradication. In addition, we summarize the recent advances in efficient antitumor treatments by genetically engineering bacteria and bacteria-based nanoparticles. Further, possible future perspectives in bacteria-based cancer immunotherapy are also inspected.

Keywords: bacteria-based cancer treatment; engineered bacteria; tumor therapy.

Figure 1

Schematic illustration showing the chemotaxis-driven delivery of NPNs for complete eradication of tumors post-phototherapy. (a) Neutrophils sense, capture, and engulf pathogens by recognizing the PAMPs with toll-like receptors (TLRs). (b) Preparation of NPNs by coating the OMVs on NPs, which inherit PAMPs from the OMVs. (c) Preparation of PEG-b-PLGA NPs encapsulating PBIBDF-BT (PBT) as a photothermal transducer. (d) The limited penetration of laser light used in PTT causes heterogeneous heat distribution within the tumor tissue and incomplete eradication of tumors, thus leading to tumor recurrence. (e) Treatment-induced cell death creates an inflammatory environment of the residual tumor and induces the production of granulocyte colony-stimulating factor (G-CSF), granulocyte–macrophage colony-stimulating factor (GM-CSF), and chemokines CXCL1 and MIP-2. #1a The released G-CSF and GM-CSF increase neutrophil production from bone marrow. #1b The released CXCL1 and MIP-2 broadcast the location of the inflamed tumor. #2 Neutrophils enter the blood circulation and encounter the injected NPNs. #3 Neutrophils sense NPNs with the recognition of LPS and lipoprotein by TLRs and subsequently engulf them. #4 Neutrophils laden with NPNs are recruited into the tumor site in response to the chemokine gradient through the following cascade: adhesion, crawling, and transmigration. #5 NPNs are released from neutrophils to kill tumor cells along with the formation of NETs in the inflamed tumor (Adapted from reference [36] with permission).

Figure 2

The attenuated Klebsiella pneumonia derived outer-membrane vesicles (OMVs), as a kind of biological drug-delivery carriers, are highly effective in transporting the chemotherapy drug doxorubicin (DOX) into nonsmall-cell lung cancer (NSCLC) A549 cells. Moreover, they can elicit appropriate immune responses, thereby enhancing the anti-NSCLC effect of DOX with no obvious toxicity in vivo (Adapted from reference [42] with permission).

Figure 3

Salmonella stimulates host immune response against tumors. Salmonella accumulates in tumors (especially in necrosis region), inhibits tumor angiogenesis, and induces apoptosis and autophagy in tumor cells. Salmonella increases and activates cytotoxic T lymphocytes, antigen presenting cells (APCs) and macrophages against tumor cells, reduces tumor infiltration of Treg cells, and ablates the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (Adapted from reference [61] with permission).

Figure 4

Design, preparation and characterization of ApCB. (a) Preparation of ApCB through amide condensation. (b) Aptamer-assisted tumor localization of bacteria for enhanced biotherapy. (c) Typical LSCM images of aptamer-conjugated bacteria. The red and green channels indicate aptamers conjugated with Cy5- and EcN-producing GFP, respectively. Images are representative of three independent biological samples. Scale bar: 10 μm. (d) Flow cytometric analysis of EcN and EcN conjugated with Cy5-labeled AS1411. (e) Percentages of conjugated EcN under different feed ratios. Error bars represent the standard deviation (n  =  3 independent experiments). Data are presented as mean values ± SD. (f) Average binding number of aptamers on each bacterial quantified by calculating the difference of fluorescent intensity of the aptamer solution after reaction. Error bars represent the standard deviation (n  =  3 independent experiments). Data are presented as mean values ± SD. (g) Bacterial viabilities of EcN, 2ApCB, 5ApCB, and 10ApCB by LB agar plate counting. Plates were incubated at 37 °C for 24 h prior to enumeration (n = 3 independent experiments). Data are presented as mean values ± SD; significance was assessed using Student’s t test (two-tailed); ns: no significance. (h) Degradation kinetics of the conjugated AS1411 in 90% phosphate-buffered serum solution at 37 °C. Error bars represent the standard deviation (n  = 3 independent experiments). Original data are provided as a Source Data file. (Adapted from reference [115] with permission).

Figure 5

The scheme of bacteria-based Fenton-like bioreactor and its chemodynamic therapy process for antitumor therapy (Adapted from reference [116] with permission).

Figure 6

A scheme illustrating the engineering of bioluminescent bacteria to boost PDT and antitumor immunity for synergistic cancer treatment. Upon i.t. injection, engineered Luc-S.T.ΔppGpp would rapidly colonize and emit bioluminescence in the presence of substrate D-luciferin as the light source to boost PDT by activating Ce6, thereby causing cell death of both cancer cells and Luc-S.T.ΔppGpp itself to release tumor associate antigens (TAAs), DAMPs (e.g., CRT), and PAMPs (1). Meanwhile, such Luc-S.T.ΔppGpp colonization could also efficiently reverse the immunosuppressive tumor microenvironments (TMEs) by promoting intratumoral frequencies of M1 macrophages and NK cells, while suppressing intratumoral frequencies of M2 macrophages and Tregs (2). As the result, such Luc-S.T.ΔppGpp as both implantable light source (in the presence of D-luciferin) and immunostimulator could elicit potent innate and adaptive antitumor immunity to effectively suppress the growth of treated tumors, inhibit tumor metastasis, and prevent against tumor recurrence (Adapted from reference [130] with permission).

Figure 7

Schematic illustration of (a) the construction of LOD/TPZ@Lips-LA microbiotic nanomedicine by bonding LA and LOD co-loaded liposome onto the lactobacillus (LA) and (b) LOD/TPZ@Lips-LA triggered immunogenic cell death (ICD) and immune activation in tumor in synergy with the TZP-triggered chemotherapy (Adapted from reference [135] with permission).

Figure 8

Schematic illustration of a novel engineered bacterium/black phosphorus quantum dot hybrid system for hypoxic tumor targeting and efficient photodynamic therapy (Adapted from reference [137] with permission).

Figure 9

Schematic depiction of utilizing LMO@RBC to improve cancer immunotherapy. (A) Schematic illustration of RBC membranes extraction and the preparation of LMO@RBC. (B) Tumor-homing LMO@RBC effectively accumulated in primary tumor after intravenous administration and triggers cancer cell pyroptosis. Pyroptotic cancer cells in primary tumor release proinflammatory substances, which induce DC maturation and T cell activation in tumor-draining lymph nodes (TDLNs), resulting in efficient suppression of primary and remote tumors (Adapted from reference [138] with permission).