Fig. 3

The mechanisms involved in the intratumoral microbiota-promoted tumorigenesis and cancer development. The intratumoral microbiota may contribute to promotion of the initiation and progression of cancers by DNA mutations, activating carcinogenic pathways, promoting chronic inflammation, complement system, and initiating metastasis. (1) DNA mutations: Toxins produced by intratumoral microbiota can directly damage host cell DNA, or indirectly damage through ROS production, which leads to genetic mutations and carcinogenesis. (2) Activating carcinogenic pathways: Some intratumoral microbiota can produce effectors (CagA and AvrA) to activate the β-catenin signaling pathway in the host cell, which induces cell growth and proliferation; Bft derived from B. fragilis stimulates E-cadherin cleavage, and FadA on the surface of F. nucleatum binds to E-cadherin on colon cancer cells, thereby activating the β-catenin signaling pathway. (3) Promoting chronic inflammation: Intratumoral microbiota can bind to pattern recognition receptors to produce a variety of cytokines and activate the NF-κB signaling pathway, thereby forming a positive cycle, leading to chronic inflammation and promoting tumor progression. At the same time, F. nucleatum can activate the TLR4/MYD88/NF-κB signaling pathway to increase miR-21 and inhibit RASA1 expression in colorectal cancer cells, thereby triggering the RAS signaling pathway to result in an increase of transcription genes related to growth and proliferation. In addition, F. nucleatum can activate TLR4 signaling pathway to increase CYP2J2, and then catalyze linoleic acid to promote the production of 12,13-EpOME, which leads to EMT and tumor formation. Moreover, P. gingivalis activates the MAPK signaling pathway through gingipain to promote cancer cell proliferation. (4) Complement system: In pancreatic duct adenocarcinoma, Malassezia’s fungal wall glycans can be recognized by MBL in the tumor environment, which activates C3 invertase to promote cell proliferation, motility, and invasiveness. (5) Initiating metastasis: Staphylococcus, Lactobacillus, and Streptococcus in breast cancer cells can inhibit the RhoA-ROCK signaling pathway to reshape the cytoskeleton and help tumor cells resist mechanical stress in blood vessels and promote hematogenous metastasis