Both‐In‐One Hybrid Bacteria Suppress the Tumor Metastasis and Relapse via Tandem‐Amplifying Reactive Oxygen Species‐Immunity Responses

Abstract

Bacterial therapy, which targets the tumor site and aims at exerting an antitumor immune response, has displayed a great potential against malignant tumors. However, failure of the phase I clinical trial of Salmonella strain VNP20009 alone demonstrates that bacterial treatment alone can unsatisfy the requirements of high efficiency and biosafety. Herein, a strategy of both-in-one hybrid bacteria is proposed, wherein the chemotherapeutic drug doxorubicin (DOX) is integrated onto the surface of glucose dehydrogenase (GDH)-overexpressed non-pathogenic Escherichia coli (E. coli) strain, to potentiate the antitumor efficacy. Nicotinamide adenine dinucleotide phosphate (NADPH), which is produced by GDH from E. coli, promotes the generation of toxic reactive oxygen species (ROS) within the tumor, and ROS is then catalyzed by the DOX-activated NADPH oxidases. Importantly, the hybrid bacteria enhance stimulated systemic antitumor immune responses, thereby leading to effective tumor eradication. When this strategy is applied in four different tumor models, the hybrid bacteria significantly inhibited tumor metastasis, postsurgical regrowth, and primary/distal tumor relapse. The both-in-one ROS-immunity-boosted hybrid bacteria strategy provides knowledge for the rational design of bacteria-based synergistic cancer therapy.

Harnessing Engineered Immune Cells and Bacteria as Drug Carriers for Cancer Immunotherapy

“…Compared to the single Dox group, the hybrid bacteria could precisely target tumors and exhibit higher tumor inhibitory efficiency since Dox was capable of activating the membrane-spanning NADPH oxidases (NOXs), which catalyze the conversion of NADPH and oxygen into NADP + and ROS (Figure d). More importantly, owing to the bacterial antigens, the engineered bacteria provoked robust immune responses via activating T-cells and increasing cytokine secretion . Recently, Pei et al proposed radioiodine-labeled bacterial vectors for cancer radio/immunotherapy.…”

Recent advances in bacteria-mediated cancer therapy

“…However, the proinflammatory ability of bacteria-induced antitumor immune response is not enough to inhibit the growth of a tumor but when combined with chemotherapy may achieve high efficiency of tumor ablation. Sun et al (2021 ) proposed a new strategy to prevent tumor metastasis and relapse by tandem-amplifying ROS-immunity responses. The chemo-drug doxorubicin (DOX) was conjugated onto the cell wall of glucose dehydrogenase (GDH)-overexpressed E. coli via bio-condensation reaction to enhance the antitumor efficacy.…”

Boarding Oncolytic Viruses onto Tumor-Homing Bacterium-Vessels for Augmented Cancer Immunotherapy

“…(ii) They can easily gather in the tumor tissue due to tumor vascular disorder. (iii) The immunosuppressive tumor microenvironment is also beneficial for bacterial proliferation. − Apart from the high tumor-homing capacity and the immunomodulatory activity, the therapeutic effect of bacteria is also promising. − For example, the facultative anaerobe Salmonella typhimurium VNP20009 can invoke strong antitumor immune responses. , Given its biosafety nature and significant antitumor effect in preclinical studies, VNP20009 was subjected to a phase I clinical trial, which failed due to its limited tumor inhibition rate and undesirable dose-dependent toxicity …”

“…13−15 For example, the facultative anaerobe Salmonella typhimurium VNP20009 can invoke strong antitumor immune responses. 16,17 Given its biosafety nature and significant antitumor effect in preclinical studies, VNP20009 was subjected to a phase I clinical trial, which failed due to its limited tumor inhibition rate and undesirable dose-dependent toxicity. 18 Considering the strengths and weaknesses of bacterial or viral therapies, it is expected that the combination of OVs and bacteria could be a strategic route toward enhanced intratumoral enrichment and augmented antitumor immune After intravenous injection of E. coli-lipo-OAs, OAs hijacked onto the tumor site along with the bacterial vehicles, thus significantly increasing the intratumoral enrichment of OAs by a factor of ∼170 compared with the conventional intravenous injection of bare OAs.…”