Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy

Abstract

Microorganisms, including bacteria, viruses, fungi, and other eukaryotes, play critical roles in human health. An altered microbiome can be associated with complex diseases. Intratumoral microbial components are found in multiple tumor tissues and are closely correlated with cancer initiation and development and therapy efficacy. 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. Moreover, the intratumoral microbiota may not only enhance antitumor immunity via mechanisms including STING signaling activation, T and NK cell activation, TLS production, and intratumoral microbiota-derived antigen presenting, but also decrease antitumor immune responses and promote cancer progression through pathways including upregulation of ROS, promoting an anti-inflammatory environment, T cell inactivation, and immunosuppression. The effect of intratumoral microbiota on antitumor immunity is dependent on microbiota composition, crosstalk between microbiota and the cancer, and status of cancers. The intratumoral microbiota may regulate cancer cell physiology and the immune response by different signaling pathways, including ROS, β-catenin, TLR, ERK, NF-κB, and STING, among others. These viewpoints may help identify the microbiota as diagnosis or prognosis evaluation of cancers, and as new therapeutic strategy and potential therapeutic targets for cancer therapy.

Fig. 1

Timeline of the history and milestones of intratumoral microbiota. The eight key research milestones of intratumoral microbiota were retrospectively summarized from 1550 BC to present day

Fig. 2

The diversity of intratumoral microbiota. Several tumors have been closely correlated with microbial infections. Each tumor type, including lung, breast, pancreas, ovary, brain, bone tumors, and melanoma, has a distinct bacterial and fungal composition. Moreover, a distinct community of microbiota between the tumor and peritumor tissues has been found

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

Fig. 4

Effects of the intratumoral microbiota on enhancing antitumor immunity. The intratumoral microbiota may enhance antitumor immunity and immunotherapy efficacy via mechanisms including STING signaling activation, T and NK cell activation, TLS production, and intratumoral microbiota-derived antigen presenting. (1) STING signaling activation: The intratumoral Bifidobacterium can activate DCs via the STING signaling pathway. A. muciniphila can produce STING agonists to induce IFN-I secretion by intratumoral monocytes, further promoting macrophage reprogramming and the crosstalk between NK and DC. (2) T and NK cell activation: The intratumoral Saccharopolyspora, Lachnoclostridium, EBV, and HBV, etc. can enhance antitumor immunity by promoting CD8⁺ T cell recruitment and activation mediated by intratumoral microbiota-derived CXCL9, CXCL10 and CCL5, which further prolongs patient survival. TMAO secreted by Clostridiales could trigger the PERK-mediated ER stress to induce tumor cell pyroptosis, which enhances antitumor immunity mediated by CD8⁺ T cells. A high-salt diet can increase Bifidobacterium and intratumoral localized, leading to enhanced NK cell function and tumor regression through the elevated by-product-hippurate. (3) TLS production: The intratumoral H. hepaticus induces Tfh cell- and B cell-dependent antitumor immune responses, which drives the maturation of tertiary lymphoid structures. (4) Intratumoral microbiota-derived antigen presenting: Furthermore, bacterial antigens can be seized by tumor cells or DCs, which further induces the responses of tumor-specific T cells

Fig. 5

Effects of the intratumoral microbiota on decreasing antitumor immunity. The intratumoral microbiota may not only enhance antitumor immunity but also decrease antitumor immune responses and promote cancer progression through pathways including upregulation of ROS, promoting an anti-inflammatory environment, T cell inactivation, and immunosuppression. (1) Upregulation of ROS: B. fragilis and Fusobacterium can result in tumor progression via the production of ROS, which regulates immune responses and local inlfammation to promote tumor progression. (2) Promoting an anti-inflammatory environment: IL-17 secreted from intratumoral bacteria can promote the infiltration of intratumoral B cells that mediate tumor growth. Bacteria in tumor tissues may modulate the local anti-inflammatory tumor microenvironment by the production of IL-1β and IL-23 from myeloid cells, which leads to high levels of IL-17 derived from γδT cells, contributing to tumor progression. The fungi in tumor tissues can enhance IL-33 secretion from cancer cells to recruit Th2 and ILC2 cell infiltration, leading to tumor progression. (3) T cell inactivation: In addition, the intratumoral F. nucleatum and Methylobacterium may decrease the density of tumor-infiltrated T cells and promote T cell dysfunction in tumor tissues to induce tumor progression. (4) Immunosuppression: Lastly, intratumoral N. ramosa, S. aureus, HBV and HCV can enhance immunosuppression by Tregs to mediate cancer development. The bacteria can program TAMs via the TLR signaling pathway, increase MDSCs, and inhibit Th1 cell differentiation to mediate immune tolerance. Commensal fungi can increase TAMs and decrease T cells to inhibit the antitumor immune responses

Fig. 6

Signaling pathways involved in the influence of intratumoral microbiota on tumor biology and immune response. Intratumoral microbiota may regulate cancer cell physiology and the immune response by different signaling pathways, including β-catenin, TLR, ERK, NF-κB, and STING. (1) β-catenin signaling: The products of Salmonella, F. nucleatum and B. fragilis can directly or indirectly activate the β-catenin signaling through E-cadherin-mediated phosphorylation, thus triggering β-catenin to translocate into the nucleus and activate TCF, which stimulates downstream target gene transcription and leads to cell proliferation. (2) TLR signaling: F. nucleatum can bind to TLR4 on tumor cells to activate the AKT and NF-κB signaling; gram-negative bacteria-derived LPS can also be recognized by TLR4, which further triggers the NF-κB signaling pathway. (3) ERK signaling: Both F. nucleatum-activated NF-κB signaling pathway and gingipain produced by P. gingivalis can stimulate the RAS-RAF-MEK-ERK signaling cascade. (4) NF-κB signaling: Microbiota can activate NF-κB through the β-catenin or TLR signaling pathway, and Bft-mediated MAPK signaling pathways can also activate NF-κB to induce inflammatory cytokine production. (5) STING signaling: A. muciniphila can produce c-di-AMP to activate the STING/IRF3/IFN-I signaling pathway, which induces the polarization of anti-tumor macrophage; Bifidobacterium can activate the STING signaling pathway to induce DC priming either by bacterial DNA-induced cGAS recognition or other bacterial products