Awareness of intratumoral bacteria and their potential application in cancer treatment

Abstract

Hitherto, the recognition of the microbiota role in tumorigenesis and clinical studies mostly focused on the intestinal flora. In contrast to the gut microbiome, microorganisms resident in tumor tissue are in close contact with cancer cells and therefore have the potential to have similar or even different functional patterns to the gut flora. Some investigations have shown intratumoral bacteria, which might come from commensal microbiota in mucosal areas including the gastrointestinal tract and oral cavity, or from nearby normal tissues. The existence, origin, and interactions of intratumoral bacteria with the tumor microenvironment all contribute to intratumoral microorganism heterogeneity. Intratumoral bacteria have a significant role in tumor formation. They can contribute to cancer at the genetic level by secreting poisons that directly damage DNA and also intimately related to immune system response at the systemic level. Intratumoral bacteria have an impact on chemotherapy and immunotherapy in cancer. Importantly, various properties of bacteria such as targeting and ease of modification make them powerful candidates for precision therapy, and combining microbial therapies with other therapies is expected to improve the effectiveness of cancer treatment. In this review, we mainly described the heterogeneity and potential sources of intratumoral bacteria, overviewed the important mechanisms by which they were involved in tumor progression, and summarized their potential value in oncology therapy. At last, we highlight the problems of research in this field, and look forward to a new wave of studies using the various applications of intratumoral microorganisms in cancer therapy.

Keywords: Intratumoral bacteria; Microbial community heterogeneity; Microbiome; Omics technology; cancer treatment.

Fig. 1

Multi-omic study strategy of microorganisms within tumors. Blood, stool, and tumor tissue samples obtained from longitudinal study cohorts are subjected to DNA or RNA extraction to gather host and microbial sequence data by different sequencing platforms and means. Smear and fluorescence staining may confirm the presence of microbes, while animal tests can confirm their function, MALDI-TOF cultiromics can identify microorganisms, and western blot can offer proteomics data. Combined multi-omics analysis techniques generate data from different domains, which in turn allow better study of host–microbiota interactions and explain the diversity of human microbe. On the other hand, from collecting specimens to performing gene sequence assays and then analyzing the data, there is a possibility of various contaminations. In the figure we propose corresponding contamination correction measures for the steps that are prone to contamination during pro-processing (created with BioRender.com)

Fig. 2

Heterogeneity of microorganisms within the tumor and potential sources. a Potential sources of intratumoral bacteria; b coexistence of TME and intratumoral bacteria; c–f heterogeneity of intratumoral microorganisms. In Figure d, classic and mixed pancreatic cancer tumors had similar microbiome compositions at the genus level, whereas basal-like tumors had a considerably distinct microbiome profile. The base-like subtype was significantly abundant in Acinetobacter, Pseudomonas, and Sphingopyxis (created with BioRender.com)

Fig. 3

Carcinogenic mechanisms of microorganisms within tumors. Extensive involvement of the immune system in the pro-tumorigenic role of intratumoral microorganisms: The bottom left is about intratumoral microorganisms providing antigenicity and adjuvant properties, and he bottom right section is about the origin of TAM and its dual role in tumor progression. a Theoretical models for the involvement of intratumoral microorganisms in tumor development. It is notice that in the absence of other mutations, only the helicobacter pylori bacteria that cause cancer was identified as a key driver. Some other bacteria with carcinogenic properties have also received considerable attention, such as Fusobacterium nucleatum, Escherichia coli and Bacteroides fragilis, however further studies are needed to clarify the causal relationship between these bacteria and cancer; b intratumoral bacteria promote cancer development through toxin damage to DNA; c inflammatory inducers and associated sensor pattern recognition receptors that form chronic inflammation. PAMP pathogen-associated molecular pattern, DAMP damage-associated molecular pattern, PRR pattern recognition receptor, TAA tumor-associated antigen, SCF stem cell factor, GM-CSF granulocyte-macrophage colony-stimulating factor, G-CSF granulocyte colony-stimulating factor, VEGF vascular endothelial growth factor, M-CSF macrophage-stimulating factor, CMP common myeloid progenitor, MDSCs myeloid-derived suppressor cells, TAMs tumor-associated macrophages (created with BioRender.com)

Fig. 4

The value of intratumoral bacteria in oncology treatment. a Effect of intratumoral bacteria on chemotherapy, radiotherapy and immunotherapy; b combination of bacteriotherapy and cancer treatment (created with BioRender.com)