The tumor microbiome in cancer progression: mechanisms and therapeutic potential

Abstract

The tumor microbiome (TM) comprises diverse microbial communities, such as bacteria, fungi, and viruses. Recent advancements in microbial sequencing technologies have improved our understanding of the distribution and functional roles of microbes in solid tumors. The TM is formed through several mechanisms, such as direct invasion of mucosal barriers, diffusion from adjacent normal tissues, metastasis of tumor cells, and dissemination via blood and lymphatic circulation. Microbes play a critical role in the tumor microenvironment (TME), and the TM has a heterogeneous composition in different types of cancer. This heterogeneity affects tumor development, progression, and response to treatment. The TM modulates tumor cell physiology and immune responses via several signaling pathways, such as WNT/β-catenin, NF-κB, toll-like receptors (TLRs), ERK, and stimulator of interferon genes (STING). Extensive studies have characterized the role of TM in tumor progression, revealing the importance of genetic abnormalities, epigenetic changes, metabolic regulation, invasion and metastasis, and chronic inflammatory responses. The role of TM in cancer treatment, especially in immunotherapy, has received increasing attention, demonstrating significant regulatory potential. This review provides an in-depth overview of the development of TM detection technologies, explores its potential origins and heterogeneity, and elucidates the mechanisms by which TM contributes to tumorigenesis or tumor suppression. Furthermore, this review explored how TM can be used in cancer treatment, offering a comprehensive perspective on targeted and personalized approaches.

Keywords: Cancer progression; Immune regulation; Microbial metabolites; Therapeutic interventions; Tumor microbiome.

Fig. 1

Niche and origin of the TM. (A) Multi-directional niche sharing of the microbiome among different organs. (B) Mucosal barrier invasion. The microbiome invades and colonizes the tumor through the damaged mucosal barrier. (C) Normal adjacent tissue (NAT). The microbial composition of tumor tissue is highly similar to that of NAT. (D) Concomitant tumor co-metastasis. The microbiome can migrate with the primary tumor to the site of the metastatic tumor. (E) Circulatory system transmission. The microbiome potentially migrates and colonize tumors via blood or lymphatic pathways. CRC, Colorectal cancer; TM, Tumor microbiome; TME, Tumor microenvironment; PMN, Premetastatic niche; ICT, Immune checkpoint blockade therapy; MLNs, Mesenteric lymph nodes

Fig. 2

TM coordinates multiple signal transduction cascades affecting cancer progression and participates in immune regulation. WNT/β-catenin signaling: H. pylori, Salmonella, and B. fragilis elicit β-catenin signaling activation through E-cadherin-mediated phosphorylation events, which indirectly or directly stimulate downstream gene transcription, driving cellular proliferation, migration, and invasion; TLR signaling: F. nucleatum LPS is recognized by TLR4, triggering the TLR4/M MyD88 cascade and activating the NF-κB pathway to promote chronic inflammation; MERK signaling: P. gingivalis derived gingipains stimulate the RAS-RAF-MEK-ERK signaling cascade; PI3K signaling: E6/E7 oncoproteins of HR-HPV contribute to changes in the PI3K/AKT/mTOR signaling pathway, facilitating cell growth and proliferation; STING signaling: LGG induces IFN-I production via the cGAS-STING-TBK1-IRF7 cascade in DCs, while Akk activates the STING/IRF3/IFN-I pathway with c-di-AMP to polarize anti-tumor macrophages. CagA, Cytotoxin-associated gene A; BFT, Bacteroides fragilis toxin; TCF, T-cell factor; c-Myc, Cellular Myelocytomatosis oncogene; MMPs, Matrix metalloproteinases; RMI2, RecQ-mediated genome instability protein 2; BXD, Banxia Xiexin Decoction; AvrA, Avirulence protein A; TLR, Toll-like receptor; LPS, Lipopolysaccharide; MYD88, Myeloid differentiation primary response protein 88; EpOME, Epoxy-Octadecenoic Acid; ETBF, Enterotoxigenic Bacteroides fragilis; NFAT5, Nuclear Factor of Activated T-cells 5; JMJD2B, JmjC-domain-containing histone demethylase 2 B; NANOG, Nanog homeobox; SOX2, Sex-determining region Y-box 2; DCs, Dendritic cells; STING, Stimulator of interferon genes

Fig. 3

Mechanisms of the TM affecting cancer progression. (A) Gene structural abnormalities and epigenetic modifications. (B) Secretion of TM metabolites affects TME. (C) Promotion of tumor invasion and metastasis. (D) TM dysbiosis triggers carcinogenesis associated with inflammation. SCFAs, Short-chain fatty acids; LCA, Lithocholic acid; AhR, Aryl hydrocarbon receptor; EMT, Epithelial–mesenchymal transition; ICAM-1, Intercellular Adhesion Molecule-1; ALPK1, Alpha Kinase 1; ROS, Reactive oxygen species; NICD, Notch intracellular domain; TLRs, Toll-like receptors

Fig. 4

TM-involved applications in cancer therapy. (A) Engineered bacteria exert a significant anti-tumor effect by producing cytotoxic molecules, converting prodrugs with specialized enzymes, delivering therapeutic payloads, and activating the immune response. Role of C. novyi-NT in targeted therapy within the hypoxic and necrotic regions of tumors. (B) OVs trigger ICD, releasing tumor-associated antigens and initiating an anti-tumor immune response. OVs equipped with cytokines can remodel the TME. The combined strategy of OVs with ICI and CAR-T cells can enhance therapeutic activity. (C) Antibiotics and bacteriophages manipulate the TM to achieve the targeted elimination of the carcinogenic microbiome.LLO, Listeriolysin O; TNFα,Tumor necrosis factor-α; TAAs, Tumor-associated antigens; PD-L1, Programmed death ligand 1, CTLA4, Cytotoxic T-lymphocyte-associated protein 4; PLC, Phospholipase C; BGNP, Branched gold nanoparticles; ITME, Immunosuppressive tumor microenvironment; ICD, Immunogenic cell death; ICI, Immune checkpoint inhibitor; TCR, T cell receptor; MHC, Major Histocompatibility Complex; PAMPs, Pathogen-associated molecular patterns; DAMPs, Damage-associated molecular patterns; DCs, Dendritic cells; OVs, Oncolytic viruses; CAR-T, Chimeric antigen receptor T-cell