Skip to main content
Download PDF

Intratumoral microbiota in colorectal cancer: focus on specific distribution and potential mechanisms

Cell Communication and Signaling volume 22, Article number: 455 (2024) Cite this article

Abstract

Colorectal cancer (CRC) is one of the most prevalent and lethal malignant tumors globally, posing significant health risks and societal burdens. Recently, advancements in next-generation sequencing technology have identified CRC intratumoral microbiota, thereby opening up novel avenues for further research. This review synthesizes the current advancements in CRC intratumoral microbiota and their impact on CRC progression and discusses the disparities in the relative abundance and community composition of CRC intratumoral microbiota across various colorectal tumors based on their anatomical location and molecular subtypes, as well as the tumor stages, and spatial tumor distribution. Intratumoral microbiota predominantly influence CRC development by modulating colonic epithelial cells, tumor cells, and the tumor microenvironment. Mechanistically, they can cause DNA damage, apoptosis and epithelial-mesenchymal transition. The effects of different intratumoral microbiota on CRC have been shown to be two-fold. In the future, to address the limitations of existing studies, it is important to develop comprehensive experimental protocols and suitable in vitro models for elucidating more mechanisms of intratumoral microbiota on CRC, which will facilitate the clinical application of microbe-related therapeutic strategies in CRC and potentially other tumors.

Colorectal cancer (CRC) is the third most prevalent malignant tumor globally, with the third highest incidence and second highest mortality rates, thereby representing the most prevalent malignancy in the digestive system [1]. Due to significant lifestyle alterations impacting microorganisms, with a notable trend towards a younger demographic affected by CRC [2]. The hypoxic and nutritionally rich immunosuppressive milieu within CRC tissues provides an opportune environment for microbial survival. Microorganisms can coexist with host cells in various bodily regions, such as the skin, mouth and gastrointestinal tract, exerting influence on both physiological and pathological processes. Previous investigations have underscored the pivotal role of microorganisms in influencing tumorigenesis, progression, and prognosis [3, 4].

Bacteria were initially identified in tumor tissues over a century ago. However, the recognition of intratumoral microbes has been limited by challenges such as ineffective decontamination methods, the extremely low abundance of microbes within tumors, and substantial interference from host DNA. The advent of next-generation sequencing technologies has revolutionized research on intratumoral microbes. In 2020, Nejman et al. [5] examined 1,526 tumor tissues and adjacent normal tissues across seven cancer types and observed characteristic intratumoral microorganisms in different tumors, primarily located within tumor cells and immune cells. Similarly, in 2022, Narunsky-Haziza et al. [6] detected fungi in all 35 tumor tissues, predominantly within tumor cells. Anders B et al. [7] also reported the presence of fungi in gastrointestinal tumors, with a high abundance of Candida and Yeasts notably associated with gastrointestinal cancers. With the rapid advancement of intratumor microbial detection and analysis techniques, recent studies have elucidated the spatial distribution and localized effects of intratumoral microbes and explored interactions between host cells and microbes at spatial, cellular, and molecular levels. These investigations suggest that microbial distribution within tumors is not random but rather organized into microecological niches that influence CRC progression by modulating functions such as immune and epithelial cells [8].

This review synthesizes recent research on intratumoral microorganisms enriched in CRC and their impact on the disease to stimulate further exploration of microorganisms in colorectal tissues as potential biomarkers for CRC diagnosis, treatment, and prognosis.

Potential sources and detection methods of intratumoral microbiota in CRC

Α-diversity and β-diversity are two important measures of microbial community diversity. α-diversity refers to the species richness of microorganisms within a single sample, while β-diversity refers to the differences in microbial composition between samples. CRC intratumoral microorganisms exhibit decreased α-diversity and increased β-diversity compared to normal controls [9], which is characterized by an increased abundance of Proteobacteria, Fusobacteria, Campylobacteria, and Spirochaetes, alongside a decreased abundance of Bacteroidetes, Firmicutes, Verrucomicrobia, Actinobacteria, and Euarchaeota in tumor tissues [10].

Potential sources of intratumoral microbiota in CRC

Colorectal intratumoral microorganisms primarily originate from the intestines, the oral cavity and adjacent normal tissues, where intestinal mucosal damage and blood circulation facilitate their colonization within tumors (Fig. 1). The large number of microorganisms in the gut serves as an important source of intratumoral microorganisms in CRC. Research indicates that disruptions in the intestinal mucosal barrier, induced by various factors, facilitate the infiltration of intestinal microorganisms into colonic tissues [4]. Additionally, blood circulation helps transfer oral microorganisms to CRC tissues. Younginger et al. [11] conducted transcriptome analysis on 807 CRC samples, revealing 17 intratumoral bacteria originating from the oral flora, including Fusobacterium, morbillorum, Parvimonas micra, and Peptostreptococcus stomatis (P. stomatis). In addition, studies have revealed that intratumoral Escherichia coli (E. coli) can disseminate to the liver via the compromised intestinal vascular barrier, promoting the establishment of a hepatic "pre-metastatic ecological niche" and thereby facilitating hepatic metastasis from primary CRC [4]. Thus, blood circulation serves not only as an important conduit for microorganisms to colonize cancerous tissues but also as an essential route for mediating tumor cell metastasis to distant sites. Thus, investigating the microbial composition of various sites aids in identifying microorganisms significantly associated with CRC development. Circulating microbial DNA (cmDNA) in tumor patients mainly originates from microbial translocation such as oral cavity or intestinal tract, passive release of endogenous microbial DNA following cell death, and active secretion by cells. cmDNA has specific biological characteristics and has the potential to become a biomarker for tumors, and various researches have shown that early screening for tumors can be performed through the detection of cmDNA [12, 13]

Fig. 1
figure 1

Potential sources and detection methods of intratumoral microbiota in CRC. a Three potential source of intratumoral microbiota in CRC; b The detection methods of intratumoral microbiota in CRC. Graphics created using BioRender.com

Full size image

The process by which microbes invading tumors is intricate and involves a multitude of pathways. Intestinal microorganisms can penetrate tumor tissues through compromised intestinal mucosa. For example, Tjalsma et al. [14] proposed the "Driver-passenger" model, according to which Enterotoxigenic Bacteroides fragilis (ETBF) serves as the "driver" bacteria, actively colonizing and invading the colon, causing damage and creating conducive conditions for "passenger" bacteria to infiltrate and establish within the tumor microenvironment. For oral microorganisms, it has been observed that Fusobacterium nucleatum (Fn) is significantly enriched in CRC. Further studies revealed that Galactose-N-acetylgalactosamine (Gal-GalNAc), which is overexpressed in CRC cells, can be recognized by bacterial fibroblast activation protein (Fap) and promote Fn colonization in CRC tissue through the blood-borne transmission pathway [15]. Another study suggests that P stomatis can bind to integrin α6/β4 receptors on the surface of CRC cells through its surface protein fructose-1,6-diphosphate aldolase, promoting the adhesion and colonization of P. stomatis in the intestine [16].

Detection methods of intratumoral microbiota in CRC

Advancements in detection methods have enabled a comprehensive analysis of all microorganisms without the necessity for culture (Fig. 1). Techniques such as immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and D-alanine-based assays are commonly used for detecting intratumoral microorganisms [17]. 16S rRNA sequencing and macrogenomic sequencing are the primary methods utilized to characterize microbial composition and abundance. While 16S rRNA sequencing is the main tool for microbiome characterization, its utility in tumor tissues, where microbial abundance is notably low, remains limited. Nejman et al. [5] addressed this limitation by developing the 5R 16 s sequencing protocol for amplifying five regions on the 16S rRNA gene. By amplifying 68% of the bacterial 16S rRNA gene using short amplicons, this method enhances the coverage and resolution of bacterial species detection and proves to be more advantageous for intratumoral microbial detection compared to the conventional V4 or V3-V4 amplification commonly employed for 16S rRNA analysis. Macrogenomics employs high-throughput sequencing of genomic DNA from all microorganisms in a sample, enabling not only the analysis of microbial abundance and diversity but also of colony function and associated metabolic pathways. Additionally, the integration of multi-omics represents the primary research approach for functional analysis of intratumoral microorganisms [8, 18,19,20]. For instance, SAHMI, a single-cell analytical method, investigates host-microbe interactions at the single-cell level by denoising single-cell sequencing data and recovering microbial signals [19]. Additionally, INVADE seq can identify bacteria in host cells by targeting conserved regions of 16S rRNA with primers. When coupled with spatial genomics, it reveals microbial distribution in the tumor microenvironment, providing insights into host cell-microbe interactions across spatial, cellular, and molecular levels [20].

Intratumoral microbiota in colorectal tumors

Intratumoral microbiota in different molecular subtypes of CRC

Consensus molecular subtypes (CMSs) of CRC is a classification based on the molecular characteristics of tumors, which classifies CRC into four distinct subtypes, each with different biological characteristics, clinical manifestations and therapeutic responses [21]: CMS1 immune subtype: characterized by histology exhibiting massive lymphocytic infiltration, with microsatellite instability being common. CMS2 tumorigenic subtype: exhibits activation of WNT and MYC signal pathways and higher chromosomal instability. CMS3 metabolic subtype: demonstrates significant metabolic dysregulation, often accompanied by a high frequency of K-RAS mutations. CMS4 mesenchymal subtype: shows enhancements in both immunosuppressive and fibrotic responses. The different molecular subtypes of CRC display variations in intratumoral microbial composition and abundance. Younginger et al. [11] observed that the relationship between Fusobacterium animalis (Fa) and tumor gene expression varied by CMS through transcriptome analysis of colon tumor tissues. Differentially expressed genes in CMS1 and CMS2 tumors are strongly associated with Fa. Another study performed 16S rRNA sequencing of tumor and paracancerous tissues from 423 patients with stage I-IV CRC to categorize CRC in terms of oncomicrobial community subtypes (OCS) [10]. The results showed that 21% were OCS1, enriched for oral pathogens such as Fusobacteria, exhibiting high CRC grade, positive MSI-H, CpG island methylation phenotypes, and commonly containing BRAF V600E and FBXM7 mutations. Additionally, 44% were OCS2, enriched with Firmicutes and Bacteroidetes, and 35% were OCS3, enriched with Escherichia and Shigella, associated with chromosomal instability. Byrd et al. [22] also found higher abundance of Alisterella, Casatella, and Fusobacteriaceae in tumor tissues with high microsatellite instability. Fn is also preferentially enriched in CRC tumor tissues with KRAS p.G12D mutations, and it promotes tumor progression of KRAS p.G12D mutant CRC by binding to DEAH-box helicase 15 [23].

Dynamic changes of Intratumoral microbiota during the evolution of CRC

Dynamic changes in intratumoral microbial composition are closely associated with CRC progression. During colorectal adenoma-carcinoma evolution, the adenoma stage high-variable microbe (HVM) was found to be mainly Ascomycota (43.14%). However, the proportion of Ascomycota gradually declined with adenoma-carcinoma progression, being supplanted by the Firmicutes (54.0%). Additionally, the number of HVMs within the tumor decreased along the adenoma-carcinoma evolution [24]. This study underscores the heterogeneity of microbial communities within colorectal tumors or precancerous adenomas, highlighting their significant association with adenoma-carcinoma sequence changes. The “Driver passenger” model divides CRC into four stages of development: normal, hyperplasia, adenoma, and tumor. During the four developmental stages of CRC, "driver" bacteria predominantly manifest in the early phases, where they alter the intestinal microenvironment and facilitate the colonization of "passenger" bacteria. These "passenger" bacteria become enriched in the later stages of CRC progression, encompassing some opportunistic pathogens and even probiotics [14]. Therefore, intratumoral microbial detection has the potential to differentiate the developmental stages of CRC. For instance, Geng et al. [25] used 454 pyrosequencing of bacterial 16S rRNA genes associated with normal, adenoma, and tumor biopsy samples, and found 7 potential “driver” bacterial genera and 12 potential “passenger” bacterial genera.

Furthermore, the research also revealed that the composition and abundance of microbes in tumor tissues vary at different stages of malignancy. The ratio of Candida to yeast is usually lower in early-stage CRC, but it significantly increases in stage IV tumors [26]. In addition, the abundance and composition of CRC intratumoural microorganisms differed in TNM staging. Mira-Pascual et al. [27] analyzed the relationship between tumor stage and microbiota composition. They found that the abundance of Staphylococcus was lower in T2 and T3 tumors, while the abundance of Streptococcus was higher in T3 tumors. Fn is notably enriched in CRC tissues, closely linked to CRC proliferation and metastasis, and can serve as a predictive molecule for the course of CRC disease [28]. Fn was found to account for 5.9% of adenoma tissue, escalating to 81.8% as CRC progressed to III/IV stages [29].

Distribution of the intratumoural microbiota in right and left colon and rectum tumors

Left and right colon tumors differ significantly in a number of ways, these include epidemiological features, clinical presentation, molecular features, response to treatment, and prognosis. It was found that the composition and abundance of intratumoural microbial vary among tumors in right and left colon. Studies have shown that right-sided tumors are more homogeneous in microbial composition and more likely to lead to a poor prognosis [30, 31]. Nardelli et al. [11] found that Alistipes spp., Bacteroides spp. and Parabacteroides distasonis were significantly more abundant in the right colon [32]. Mouradov et al. [10] found that tumors enriched with oral pathogens such as Fusobacteria occurred more often in the right side of the colon, whereas tumors enriched with Firmicutes, Bacteroidetes, Escherichia, or Shigella developed in the left side of the colon. Due to the differences in microbes within tumors of the right and left colon, some researchers have identified important microbial and genomic biomarkers by constructing mathematical models to distinguish between right and left CRCs [33]. In their model, it was also found that Ruminococcus gnavus, Clostridium acetereducens, Lachnospiraceae, and Ruminococcus sp. were enriched in the right colon, and Akkermansia muciniphila were enriched in the left colon. In addition, Alves et al. [34] found that pks+E.coli, which belongs to Proteobacteria, was enriched in right-sided colon and that patients with pks+E.coli had lower survival. Similarly, it was also found that patients with Fn-enriched right-sided colon had shorter progression-free survival times [35]. Research has indicated that in rectal tumors, certain bacterial genera are more prevalent. Specifically, rectal-cancer samples exhibit higher levels of Bacteroides, Phascolarctobacterium, Parabacteroides, Desulfovibrio, and Odoribacter. In contrast, non-cancerous samples show a higher prevalence of Pseudomonas, Escherichia, Acinetobacter, Lactobacillus, and Bacillus [36].

Distribution of CRC intratumoral microbiota in different spatial locations of the tumor

Li et al. [37] observed significant differences between microbiota in tumor tissues and normal tissues from the same patient source but no notable differences in microorganisms between tumor and paracancerous tissues, or between paracancerous and normal tissues. These findings suggest that paracancerous microorganisms may represent a transitional state between tumor and normal tissue microorganisms. Thus, the microbial composition varies heterogeneously across different sites within the same tumor. Several studies on CRC intratumoral microorganisms have sampled multiple sites within the same tumor tissue and paired normal tissues for testing and analysis due to differences in microbial composition at various tissue sites [24, 38, 39]. Nonetheless, it has also been demonstrated that the variation in microbiome α-diversity among individual samples exceeds the variation within individual samples. Due to the extremely low levels of intratumoural microorganisms and the influence of environmental microorganisms, the existence of differences in microorganisms at different sites of the same sample needs to be confirmed with more and more precise clinical samples.

Currently, the existing research on the enrichment of intratumoral microbes in left-sided and right-sided CRC are relatively common and consistent. However, the evidence of associations between types of intratumoral microorganisms and different cancer subtypes and stages is still limited. In addition, current studies tend to concentrate on the disparities in the abundance of single intratumoral microorganism in different molecular subtypes or the abundance of intratumoral microbes in a single molecular subtype, lacking comprehensive and systematic research. Particularly, the trends in the changes of intratumoral microbiota during the process of transformation from colorectal adenoma to carcinoma or inflammatory carcinoma may be inconsistent. During tumor staging, the methodologies vary, some studies categorize based on stages I-IV, while others utilize the TNM staging system. This diversity in staging criteria has also influenced the synthesis and generalization of the overall patterns of intratumoral microbial abundance changes throughout the progression of CRC, as gleaned from an already limited body of literature.

CRC intratumoral microorganisms vary in composition and abundance across different parameters such as tumor subtypes, stages of adenoma-carcinoma progression, tumor tissues of distinct segments, and colon tumor tissues (Fig. 2). Additionally, these variations extend to factors like age of onset [40] and gender [41]. Consequently, a multitude of factors must be taken into account when sampling intratumoral microorganisms, particularly regarding the timing and location of the sampling Table 1 provide a characterization of intratumoral microorganisms in CRC.

Fig. 2
figure 2

Intratumoral microorganisms enriched in colorectal tumors. a Intratumoral microbiota in different molecular subtypes of CRC; b Dynamic changes of Intratumoral microbiota during the evolution of CRC; c Distribution of the intratumoural microbiota in right and left colon and rectum tumors; d Sampling of CRC intratumoral microbiota in different spatial locations of the tumor. Graphics created using BioRender.com

Full size image
Table 1 Characterization of the intratumoral microbiota in CRC
Full size table

Influence of intratumoral microbiota on CRC

The main microorganisms enriched in CRC tumors include Fn, pks+E.coli and ETBF. Among these, ETBF mainly affects the early stage of CRC and promotes its progression. ETBF contributes to CRC by modulating CAC immune cells [62], inducing epigenetic changes [63]. pks+E.coli causes DNA damage in colonic epithelial cells primarily through the production of the genotoxin colibactin, which leads to carcinogenesis. The effects of Fn on CRC are mainly focused on the development of CRC, including the formation of tumor microenvironment and tumor metastasis. In addition, other intratumoral microorganisms promote or inhibit the development of CRC through different biological pathways. Overall, intratumoral microorganisms exert their influence on CRC development by impacting intestinal epithelial cells, tumor cells, and the tumor microenvironment. Their mechanisms of action involve processes such as DNA damage, apoptosis, and epithelial-mesenchymal transition. Notably, different intratumoral microorganisms exhibit dual characteristics in their effects on CRC.

Effect of intratumoral microbiota on intestinal epithelial cells

DNA damage is a key driver in CRC development, and bacterial toxin production by intratumoral microorganisms acts directly on cells to cause DNA damage. pks+E.coli is closely associated with DNA damage in CRC and produces the genotoxin colibactin, which causes the cells to undergo two types of characteristic DNA mutations: single base substitutions and indels. Using human intestinal organoids as a model, some researchers have found that single-base substitutions (T > N) induced by colibactin are frequently observed in ATN and TTT sequences [64]. Moreover, Chen et al. [65] observed enrichment of pks+E.coli in both tumor tissues and paired normal tissues compared to healthy individuals. CRC patients exhibited a higher incidence of indels in genes closely associated with many driver mutations in CRC. Another study revealed increased DNA damage in colonic epithelial cells, accelerated tumorigenesis, and higher mortality in tumor-susceptible mice harboring both pks+E.coli and ETBF compared to mice with either pks+E.coli and ETBF alone. These results suggest that ETBF enhanced pks+E.coli colonization and DNA damage in colonic epithelial cells [66]. Additionally, research indicates that Campylobacter produces a cell-lethal expansion toxin leading to host DNA double-strand breaks [67]. Shujiro et al. [54] classified tumor samples into Campylobacter high and Campylobacter low groups based on Campylobacter abundance, revealing higher levels of host DNA mutations in the Campylobacter high group.

Effect of intratumoral microbiota on tumor cells

Regulating non-coding RNA

Interactions between intratumoural microbes and non-coding RNAs play an important role in CRC progression, which can affect tumor cell proliferation, apoptosis and metastasis (Fig. 3a). Unlike normal cells, tumor cells proliferate uncontrollably, and intratumoral microorganisms promote tumor cell proliferation. ETBF can down-regulate miR-149-3p, thereby promoting PHF5A-mediated selective splicing of KAT2A RNA in cells, leading to the trans-activation of SOD2 and ultimately contributing to CRC progression [62]. Moreover, Porphyromonas gingivalis can invade tumor cells and enhance their proliferation by activating the MAPK/ERK signaling pathway [68]. In CRC, tumor cell apoptosis is predominantly mediated by Fn. Yu et al. [69] discovered that Fn targets the TLR4/MYD88/MiR-18a*/ULK1 and TLR4/MYD88/miR-4802/ATG7 autophagy networks, activating the autophagy pathway to inhibit chemotherapy-induced apoptosis in CRC cells. Moreover, Fn can inhibit CRC cell apoptosis by impeding autophagic flux through miR-31 [70]. Intratumoral microorganisms not only promote tumor progression but also influence treatment response. Sonodynamic therapy (SDT) exhibits promising therapeutic potential as a complementary technique to conventional cancer treatment due to its deeper tissue penetration and safety profile. Qu et al. [71] developed antimicrobial nanoplatforms (Au@BSA-CuPpIX) capable of generating reactive oxygen species (ROS) and exhibiting potent anti-Fn activity under ultrasound. Au@BSA-CuPpIX induced ROS-mediated apoptosis by inhibiting Fn and reducing the level of apoptosis inhibitory protein. Furthermore, the treatment of CRC by designing nanomedicines to target and eliminate intratumoral microorganisms has emerged as a prominent research area in tumor therapy in recent years [72,73,74,75].

Fig. 3
figure 3

Effect of intratumoral microorganisms on tumor cells. a Intratumoral microorganisms regulate tumor cell proliferation and apoptosis; b Intratumoral microorganisms promote tumor epithelial-to-mesenchymal transition. Graphics created using BioRender.com

Full size image

EMT serves as the pathological foundation for epithelial-origin malignant tumor cells to acquire migratory and invasive capabilities, playing a pivotal role in CRC metastasis. Intratumoral microbes have been identified as promoters of CRC metastasis by mediating EMT (Fig. 3b). Exosomes released by microbe-infected cells participate in various aspects of tumor formation and invasion [76]. For instance, the tumor suppressor miR-122-5p is upregulated in the serum of CRC patients but downregulated in paired tumor tissues. Ex vivo and in vivo experiments have validated that Fn enhances CRC metastasis by facilitating the exocytosis of miR-122-5p, which subsequently activates the FUT8/TGF-β1/Smads axis and induces EMT [77]. Fn also prompts tumor cells to release exosomes rich in miR-1246/92b-3p/27a-3p and CXCL16/RhoA/IL-8. These exosomes, transmitted from Fn-infected to Fn-uninfected tumor cells, promote cell migration capacity, thereby fostering CRC liver metastasis [78]. Concurrently, intratumoral microorganisms metastasize to the liver along with colon cancer cells [44]. Fn additionally enhances CRC cell adhesion to endothelial cells by triggering the ALPK1/NF-κB/ICAM1 axis, thus facilitating extravasation and metastasis [79]. Moreover, it activates the TLR4/MYD88 signaling pathway, upregulating miR21 expression and consequently reducing the level of RAS GTPase-activating protein 1 (RASA1), thereby promoting CRC cell proliferation and migration [80]. Studies have also shown that Fn synergistically increases the invasiveness and EMT characteristics of CRC cells treated with dextran sulfate sodium (DSS) [81].

Metabolic reprogramming

The metabolic reprogramming is a crucial biological trait in tumor development, providing the energy and materials essential for tumor growth. Glycolysis is the main metabolic mode of tumor cells to meet their energy and macromolecule requirements. Increased glycolytic dependence also promotes tumor resistance to radiotherapy as well as triggers competition for nutrients between tumor cells and tumor-infiltrating cells. Zheng et al. [82] discovered that Fn stimulates glycolysis in cancer cells by inducing ANGPTL4 expression in CRC cells. Then, the increased ANGPTL4 levels promote Fn colonization by upregulating GLUT1 expression and glucose uptake. Fn also enhances the transcription of long non-coding RNA ENO1-IT1 by increasing the binding efficiency of transcription factor SP1 to the promoter region of lncRNA ENO1-IT1. The increased ENO1-IT1 acts as a guide for KAT7 histone acetyltransferase, promoting ENO1 histone modification and consequently enhancing tumor cell glycolysis [83]. Moreover, Fn activates the TLR4/Keap1/NRF2 pathway to elevate the expression of the tumor cell metabolic enzyme CYP2J2 and its product 12,13-EpOME, promoting fatty acid metabolism [84]. Tsoi et al. [52] found that Peptostreptococcus anaerobius (P. anaerobius) could induce reactive oxygen species (ROS) via TLR2 or TLR4 and activate the expression of Sterol-regulatory element binding protein 2 (SREBP2) to promote cholesterol synthesis, thereby promoting the proliferation of tumor cells. mRNAs related to the regulation of lipid metabolism are overexpressed in pks+E.coli-enriched tumor tissues, and imbalance of lipid metabolism also promotes CRC progression [34]. Redox reactions are present in a wide range of metabolic processes and are key to energy conversion. Lactobacillus reuteri and its metabolite rotenone, which is down-regulated in mouse and human CRC tissues, rotenone alters redox homeostasis and reduces proliferation and survival of colon cancer cells [85]. The influence of intratumoral microbes on the metabolic reprogramming of tumor cells is bidirectional. In CRC, the downregulation of the Farnesoid X receptor (FXR) disrupts bile acid (BA) metabolism, leading to alterations in the bile acids profile, which positively regulates secretory immunoglobulin A (sIgA) secretion, and the dual regulation of BAs and sIgA enhances the adhesion and biofilm formation of ETBF, consequently promoting colorectal tumorigenesis [86] (Fig. 4).

Fig. 4
figure 4

Effect of intratumoral microorganisms on metabolic reprogramming of tumor cells. Graphics created using BioRender.com

Full size image

Another aspect, intratumoral microorganisms influence the metabolism of anticancer drugs, diminishing their effectiveness. For instance, Fn induces chemoresistance to 5-fluorouracil (5-FU) in CRC cells by upregulating baculovirus inhibitor of apoptosis (IAP) 3 (BIRC3) expression through the Toll-like receptor 4 (TLR4)/NF-κB pathway [87]. Additionally, Fn activates autophagy and reduces CRC cell response to 5-FU chemotherapy by targeting TLR4 and myeloid differentiation primary response 88 (MYD88), resulting in a selective loss of miRNA expression [69]. Moreover, in colon cancer, intratumoral Gammaproteobacteria promote tumor cell resistance to gemcitabine through the synthesis of bacterial cytidine deaminase (CDDL) [88] (Fig. 4).

Effect of intratumoral microbiota on the tumor microenvironment

Inflammatory microenvironment

The microenvironment of precancerous colonic polyps exhibits enrichment with non-enterotoxin-producing Bacteroides fragilis (NTBF), with significant upregulation of lipopolysaccharide (LPS) biosynthesis genes in NTBF strains. This NTBF-enriched milieu activates TLR4, instigating localized inflammation that promotes polyp growth and colonization by additional "passenger" bacteria such as ETBF, pks+E.coli and Fn, which potentially contribute to CRC progression [89]. Additionally, pks+E.coli enhances inflammation by secreting virulence factors [90]. Intratumoral microorganisms play a dual role in inflammation in tumors, both promoting tumor development and mediating inflammation. For instance, Fn directly targets human CRC stem cells by activating CEACAM-1-dependent protein tyrosine phosphorylation signaling, leading to increased expression of CXCL1, CXCL8, and NF-kB, thereby eliciting pro-inflammatory and oncogenic responses [91]. Streptococcus gallolyticus can selectively colonize tumor cells and promote chronic inflammation and angiogenesis, thereby promoting carcinogenesis [92]. The P. anaerobius surface protein PCWBR2 can also upregulate the expression of a large number of inflammation-associated genes through direct interaction with colonic epithelial cells or tumor cells via integrin α2/β1 [93]. In addition, Helicobacter pylori, a microorganism closely associated with the development of gastric cancer, as well as Streptococcus gallolyticus induce pro-inflammatory and oncogenic responses in the colon [84, 86].

Immunity Microenvironment

Numerous studies have shown that intratumoural microbes play a key role in remodeling the tumor immune microenvironment. Multiple lines of evidence show that the higher the intratumoural microbial diversity, the fewer tumor-infiltrating lymphocytes there are in the tumor microenvironment [94,95,96]. In addition, the regulation of the tumor immune microenvironment by intratumoural microorganisms exhibits a two-fold character that enhances or promotes anti-tumor immunity and pro-tumor immunity (Fig. 5).

Fig. 5
figure 5

The impact of intratumoral microorganisms on the tumor microenvironment. Graphics created using BioRender.com

Full size image

Borowsky et al. [97] observed a negative correlation between the amount of Fn DNA in CRC tissues and the presence of CD3 + CD4 + CD45RO + cells (memory Th cells) in the tumor stroma, suggesting that Fn suppresses antitumor immunity, as evidenced by two prospective cohort studies. Another oral source bacterium, P. anaerobius, promotes tumor growth by inducing CXCL1 secretion, increasing the number of MDSC within the tumor and reducing IFN-γ + CD8 + T cells [98]. Reduced infiltration of IFNγ + CD8 + T cells was also found in pks+E.coli-enriched tumor tissues [34]. Wang et al. [50] found that Porphyromonas gingivalis recruits bone marrow-derived immune cells, induces NLRP3, caspase-1, IL1β and pro-IL1β expression, and alters the tumor immune environment to promote CRC development. Candida albicans, another microorganism found in the tumor immune microenvironment, triggers glycolysis and IL-7 secretion in macrophages, leading to IL7-induced IL-22 secretion by acting on AhRE and STAT3 in innate lymphocytes, thus fostering CRC development [26].

In contrast to the inhibitory effect of intratumor microorganisms on antitumor immunity, some microorganisms promote antitumor immunity. Zhang et al. [55] demonstrated that tissue-resident Trichosporonaceae bacteria Ruminococcus gnavus (Rg) and Blautia producta (Bp) degrade lysoglycerophospholipids, thereby attenuating their inhibition of CD8 + T cell activity and preserving the immune surveillance function of CD8 + T cells, which delays CRC progression. Indole-3-carboxylic acid, a metabolite of the probiotic Lactobacillus gallinarum, also inhibits CD4 + Treg differentiation and enhances CD8 + T cell function through modulation of the IDO1/Kyn/AHR axis and improves anti-PD1 efficacy in CRC [99]. Overacre-Delgoffe et al. [100] confirmed that Helicobacter hepaticus (Hhep) reduces the number and size of tumors in a mouse model of colitis-associated colon cancer, increases tumor-infiltrating T cells and B cells recruitment, induces more Tfh-cells, and activates tertiary lymphoid structures to promote antitumor immunity. Additionally, Bifidobacteria can enhance dendritic cell IFN-β expression via the STING signaling pathway, stimulating adaptive immune responses and enhancing the antitumor effect of anti-CD47 antibodies [101]. Bifidobacterium adolescentis, a specific strain belonging to the Bifidobacterium, also induces Decorin + macrophage infiltration into tumor tissue and inhibits CRC [102].

The potential of intratumoral microbiota in clinical application of CRC

Diagnostic value of intratumoral microbiota

Owing to the unique distribution characteristics of the intratumoral microbiota in CRC, these microbial communities exhibit significant predictive capabilities. They are adept at distinguishing cancerous tissues from normal ones and hold promise as biomarkers for the classification of molecular subtypes and the staging of CRC. For instance, OCS1 enriched with oral pathogens such as Fusobacteria, exhibiting high CRC grade, positive MSI-H, CpG island methylation phenotypes, and commonly containing BRAF V600E and FBXM7 mutations, mostly located on the right side of the colon. Additionally, OCS2 enriched with Firmicutes and Bacteroidetes, and OCS3 enriched with Escherichia and Shigella, associated with chromosomal instability and occurring on the left side of the colon [10]. Furthermore, Fn was found to account for 5.9% of adenoma tissue, escalating to 81.8% as CRC progressed to later stages [29]. It also has been observed that the ratio of Candida to Yeast is generally low in early-stage CRC but significantly increases in stage IV tumors [26]. Fecal and intratumoral microbiotas provide a dual approach to CRC diagnostics. Testing of fecal microbiota is well-suited for non-invasive, broad population screenings, whereas intratumoral microbiota analysis offers personalized insights, crucial for precision medicine [103]. Overall, identifying the microbial composition and alterations in pathological tissues can be used as an adjunct approach to the diagnosis of CRC.

Therapeutic effects of intratumoral microbiota

Chemotherapy

Intratumoral microorganisms can effectively alter the activity of CRC chemotherapy drugs. Fn induces chemoresistance to 5-fluorouracil (5-FU) in CRC cells by upregulating baculovirus inhibitor of apoptosis (IAP) 3 (BIRC3) expression through the TLR4/NF-κB pathway [87]. Additionally, Fn activates autophagy and reduces CRC cell response to 5-FU chemotherapy by targeting TLR4 and MYD88, resulting in a selective loss of miRNA expression [69]. Intriguingly, 5-FU exhibits potent inhibitory effects on Fn, while E. coli can modify 5-FU, thereby reducing its toxicity to sensitive Fn and intestinal epithelial cells [104]. Moreover, after injecting E. coli into CT26 subcutaneous transplanted tumors, it was found that E. coli can reduce the anti-tumor activity of gemcitabine; it can also activate CB1954 cytotoxicity and significantly increase the median survival time of mice [105]. In colon cancer, intratumoral Gammaproteobacteria promote tumor cell resistance to gemcitabine through the synthesis of bacterial CDDL, and combining the antibiotic ciprofloxacin with gemcitabine can effectively neutralize the impact of Gammaproteobacteria [88]. CRC intratumoral microorganisms can inhibit the activity of multi-types of chemotherapy drugs. Different bacteria may have synergistic effects, and the combination of chemotherapy drugs and antibiotics can eliminate the inhibitory effect of some bacteria on the activity of chemotherapy drugs. The diagnosis of CRC will be facilitated by monitoring differences in intratumoural microbial abundance and composition.

Immunotherapy

In addition to chemotherapy, intratumoral microorganisms also have potential impact on CRC immunotherapy [106]. The use of immune checkpoint inhibitors is an important therapeutic strategy in anti-tumor therapy. Clostridium is enriched in CRC patients who are insensitive to immune checkpoint blockade (ICB). Further research have shown that intratumoral microorganisms may affect ICB therapy by mediating tumor infiltrating immune cell (TIIC), especially mucosal-associated invariant T cells [96]. P. Anaerobius creates an immunosuppressive tumor microenvironment through a dual pathway, inducing CXCL1 secretion and recruiting MDSCs through the integrin α2 β1-NF-κB signaling pathway, and directly activating MDSCs through the secretion of lytC22, thereby weakening T cell-mediated anti-tumor immune response [98]. Furthermore, Bifidobacterium accumulated in the CRC tumor microenvironment ultimately promoted CD47-based immunotherapy by stimulating interferon gene transcription and increasing dendritic cell crosstalk in an interferon-dependent mode [101]. Thus, intratumoural microorganisms have both advantages and disadvantages for CRC immunotherapy.

Targeted therapy

Most individuals with advanced metastatic CRC are treated with a combination of chemotherapy and molecularly targeted therapies. For instance, cetuximab has been shown to extend the overall survival of patients with wild-type KRAS gene CRC, yet a significant number of patients do not derive benefits from this treatment [107]. Investigations have revealed that P. stomatis can adhere to CRC cells by binding to the integrin α6/β4 receptor through its surface protein, fructose-1,6-diphosphate aldolase, subsequently activating the Erb-B2 receptor tyrosine kinase 2 (ERBB2) and the downstream MEK-ERK-p90 signaling pathway. This activation, driven by P. stomatis, can override the blockade of epidermal growth factor receptor inhibitors such as cetuximab and erlotinib, resulting in drug resistance in KRAS mutant CRC [16]. Concurrently, studies have demonstrated that P. stomatis can also diminish the effectiveness of BRAF inhibitors like vemurafenib in BRAF V600E mutant CRC xenografts.

Other therapies

The treatment of CRC by designing nanomedicines to target intratumoral microorganisms, live bacterial therapy using bacteria as drug carriers, or oral probiotics as auxiliary treatment of CRC are all research hotspots in the field of CRC treatment in recent years. Short-chain fatty acid butyrate can downregulate the expression of adhesion-related outer membrane proteins, thereby inhibiting Fn activity in CRC tissues. Chen et al. [74]. encapsulated sodium butyrate in liposomes to make tablets, which significantly inhibited Fn and attenuated chemoresistance by intravenous injection. Intratumoral Fn promotes CRC progression and leads to chemoresistance. Although great efforts have been made to overcome Fn-induced chemoresistance by co-delivering antibacterial and chemotherapeutic drugs, improving drug loading capacity and achieving controlled release of drugs Still challenging. Yan et al. [72]. designed a new type of nanoparticle by incorporating a positively charged polymer with Fn inhibitory ability and a negatively charged oxaliplatin prodrug, which can improve the drug loading capacity and achieve controlled release of the drug. Research have also been conducted to enhance the anti-tumor activity of anti-programmed cell death 1 (PD-1) immunotherapy by oral administration of the commensal bacterium Lactobacillus rhamnosus GG (LGG) to mice with subcutaneous transplanted tumors of CRC to increase tumor-infiltrating dendritic cells and T cells [108]. A research team has also established a microbiota targeted drug delivery system Oxa@HMI Hydrogel, this system shows high efficiency in CRC targeting and colorectal retention, and excellent anti-tumor effect [109].

Prognostic potential of intratumoral microbiota

Intratumoral microorganisms have a certain predictive effect on CRC tumor metastasis and patient survival. Microbiome analysis of biopsy samples from different parts of primary CRC patients showed that Acinetobacter, Burkholderia, Corynebacterium, Cutibacterium, Flavobacterium, Pelomonas, Rheinheimera, Sphingobium, Staphylococcus and Streptococcus were the 10 most common bacterial genera in metastatic CRC tissues [95]. Xu et al. [43] obtained two clear clusters after clustering 533 CRC tissue samples. Cluster 1 has a higher relative abundance of Proteobacteria and Bacteroidetes, and cluster 2 has a higher relative abundance of Firmicutes and Actinobacteria, and the Firmicutes/Bacteroidetes ratio is significantly higher than in cluster 1. Finally, it was found that some pathogenic bacteria enriched in cluster 1 can promote the development of colorectal cancer, resulting in lower patient survival rates. In contrast, the abundance of some probiotic and anti-cancer development genera increased significantly in cluster 2. Research have also shown that patients with Fn-enriched right-sided colon cancer have shorter progression-free survival [35].

Currently, the field of intratumoral microbiota research is in its nascent phase, with limitations in the scope and depth of investigation. The majority of studies concentrate on particular microbial species, falling short of a holistic and systematic comprehension. The intricacy of the intratumoral microbiota composition is compounded by the absence of standardized protocols for sampling, processing, and analysis, leading to challenges in comparing and replicating findings across studies. This variability hampers the generalizability of research outcomes and their translation into clinical practice. Future endeavors necessitate profound exploration across various strata, encompassing foundational theories, methodological approaches, and clinical trial designs.

Current status and challenges in the study of intratumoral microbiota and colorectal cancer

Current status

In this review, we discussed the origins of CRC intratumoral microorganisms and the methods used for their detection. We described the microbial composition in different segments of the colorectum and discussed variations in CRC microbial composition across different molecular phenotypes and disease stages. We summarized how intratumoral microorganisms influence CRC progression by impacting epithelial cells, tumor cells and the tumor immune microenvironment, as well as the potential application of intratumoral microorganisms in the clinical of CRC. Based on these findings, our investigation reveals a decrease in α-diversity and an increase in β-diversity of CRC intratumoral microbiota [9], and compared with fecal microorganisms, the low biomass of CRC intratumoral microorganisms, which are relatively less affected by diet and environment, can be used together with fecal microorganisms as a target for CRC diagnosis and treatment [103]. Moreover, various intratumoral microorganisms play distinct roles in CRC progression. Some act as probiotics, inhibiting tumor progression, while others exert major functional effects at different stages of CRC progression. For instance, ETBF and pks+E.coli are mainly associated with early inflammation or DNA damage in CRC, while Fn predominantly affects advanced CRC, promoting an immunosuppressive microenvironment and tumor cell metastasis.

Cutting-edge technologies are driving advancements in intratumoral microbiology research. In constructing ex vivo and in vivo models, such as mouse intratumoral multipoint injections and organoids, researchers have tools to investigate the interaction between specific microorganisms and tumors [50, 55]. Particularly, organoid-microbe co-cultures offer a valuable platform for directly studying microbial effects on the tumor microenvironment, providing insights into their complex pathophysiological relationship [110, 111]. Furthermore, traditional antibiotic cocktails and intravenous antibiotic injections are important experimental tools for studying microbial functions [112]..At the detection level, microscopy, immunology, and multi-omics techniques are combining forces to advance intratumor microbial detection. Innovations such as the 5R 16S rDNA sequencing technology, SAHMI process, and INVADE seq methods demonstrate this integration. Therapeutically, there is a growing focus on targeting intratumoral microorganisms for CRC treatment. Strategies include designing nanomedicines to specifically target these microorganisms and exploring live bacterial therapies utilizing bacteria as drug carriers. These approaches have emerged as research hotspots in CRC detection and treatment over the past few years [72,73,74,75, 113]. By employing nano-targeted drugs that selectively act on intratumoral microorganisms, the potential adverse effects on the intestinal flora can be effectively minimized.

Challenges

Despite recent breakthroughs in intratumoral microbiology research, several limitations remain. Firstly, the low content of intratumoral microorganisms poses a challenge, requiring the exclusion of host DNA and other environmental microorganisms to enhance detection accuracy. Secondly, current research models, such as organoid-microbe co-cultures, may not fully replicate the in vivo environment, highlighting the need for more appropriate in vitro models to explore the intricate mechanisms of tumor-microbe interactions. Thirdly, the dynamic changes in composition and abundance of intratumoral microbiota throughout the CRC process necessitate consideration of factors like sampling time and site when designing experiments. Fourthly, intratumoral microorganisms mainly exist in tumor cells or immune cells, but most studies do not distinguish between intracellular and extracellular microorganisms. Whether the mechanism of action of intracellular and extracellular microorganisms is the same requires more research to further reveal. Lastly, while the dual effects of intratumoral microorganisms on CRC are the mechanisms underlying their impact on antitumor therapy remain poorly understood, impeding the clinical application of microbe-related therapeutic strategies in oncology. Thus, extensive validation through additional preclinical models and clinical trials is imperative.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed in the study.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

12，13-EpOME:

12,13-epoxyoctadecenoic acid

ATG7:

Autophagy-related protein 7

AXIN2:

Axin Inhibition Protein 2

BF :

Bacteroides fragilis

BIRC3:

Baculoviral IAP Repeat Containing 3

Bp :

Blautia producta

CDDL:

Cytidine deaminase

cmDNA:

Circulating microbial DNA

CMSs:

Consensus molecular subtypes

C-Myc:

Myelocytomatosis oncogene

CRC:

Colorectal cancer

CYP2J2:

Cytochrome P450 2J2

DSS:

Dextran sulfate sodium

E. coli :

Escherichia coli

eIF4EBP1/2:

Eukaryotic initiation factor 4F-binding protein 1/2

ERBB2:

Erb-B2 receptor tyrosine kinase 2

ENO1-IT1:

Enolase1-intronic transcript 1

ERK:

Extracellular signal regulated kinase

ETBF :

Enterotoxigenic Bacteroides fragilis

Fa :

Fusobacterium animalis

Fap:

fibroblast activation protein

Fn :

Fusobacterium nucleatum

Gal-GalNAc:

Galactose-N-acetylgalactosamine

Glut1:

Glucose Transporter 1

Hhep :

Helicobacter hepaticus

HVM:

High-variable microbe

ICAM1:

 Intercellular Cell Adhesion Molecule-1

ILC3:

 Group 3 Innate Lymphoid Cells

IHC:

Immunohistochemistry

KAT2A:

Lysine acetyltransferase 2A

MAPK:

Mitogen-activated protein kinase

MEK:

Mitogen-activated protein kinase kinase

MyD88:

Myeloid differentiation factor88

OCS:

Oncomicrobial community subtypes

P. anaerobius :

Peptostreptococcus anaerobius

P. stomatis :

: Peptostreptococcus stomatis

Pg :

Porphyromonas gingivalis

PHF5A:

PHD-finger domain protein 5A

RAF:

Rapidly accelerated fibrosarcoma

Rg :

Ruminococcus gnavus

RhoA:

Ras homolog family member A

STX12:

Syntaxin-12

TCF:

T-cell factor

TLR4:

Toll-Like Receptor4

ULK1:

UNC-51-like kinase 1

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Spaander MCW, Zauber AG, Syngal S, et al. Young-onset colorectal cancer. Nat Rev Dis Primers. 2023;9(1):21.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Song M, Chan AT, Sun J. Influence of the gut microbiome, diet, and environment on risk of colorectal cancer. Gastroenterology. 2020;158(2):322–40.

    Article  CAS  PubMed  Google Scholar 

  4. Bertocchi A, Carloni S, Ravenda PS, et al. Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver. Cancer Cell. 2021;39(5):708–24 e11.

    Article  CAS  PubMed  Google Scholar 

  5. Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria [J]. Science. 2020;368(6494):973–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Narunsky-Haziza L, Sepich-Poore GD, Livyatan I, et al. Pan-cancer analyses reveal cancer-type-specific fungal ecologies and bacteriome interactions. Cell. 2022;185(20):3789-806.e17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dohlman AB, Klug J, Mesko M, et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022;185(20):3807–22 e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Galeano Niño JL, Wu H, Lacourse KD, et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature. 2022;611(7937):810–7.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhao L, Cho WC, Nicolls MR. Colorectal cancer-associated microbiome patterns and signatures. Front Genet. 2021;12: 787176.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mouradov D, Greenfield P, Li S, et al. Oncomicrobial community profiling identifies clinicomolecular and prognostic subtypes of colorectal cancer. Gastroenterology. 2023;165(1):104–20.

    Article  CAS  PubMed  Google Scholar 

  11. Younginger BS, Mayba O, Reeder J, et al. Enrichment of oral-derived bacteria in inflamed colorectal tumors and distinct associations of Fusobacterium in the mesenchymal subtype. Cell Rep Med. 2023;4(2): 100920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chen H, Ma Y, Liu Z, et al. Circulating microbiome DNA: an emerging paradigm for cancer liquid biopsy. Cancer Lett. 2021;521:82–7.

    Article  CAS  PubMed  Google Scholar 

  13. You L, Zhou J, Xin Z, et al. Novel directions of precision oncology: circulating microbial DNA emerging in cancer-microbiome areas. Precis Clin Med. 2022;5(1):pbac005.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tjalsma H, Boleij A, Marchesi JR, et al. A bacterial driver-passenger model for colorectal cancer: beyond the usual suspects. Nat Rev Microbiol. 2012;10(8):575–82.

    Article  CAS  PubMed  Google Scholar 

  15. Abed J, Emgård JE, Zamir G, et al. Fap2 mediates fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe. 2016;20(2):215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Huang P, Ji F, Cheung AH, et al. Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK. Cell Host Microbe. 2024;32(8):1365–79 e10.

    Article  CAS  PubMed  Google Scholar 

  17. Xue C, Chu Q, Zheng Q, et al. Current understanding of the intratumoral microbiome in various tumors. Cell Rep Med. 2023;4(1): 100884.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Poore GD, Kopylova E, Zhu Q, et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature. 2020;579(7800):567–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zheng W, Zhao S, Yin Y, et al. High-throughput, single-microbe genomics with strain resolution, applied to a human gut microbiome. Science. 2022;376(6597):eabm1483.

    Article  CAS  PubMed  Google Scholar 

  20. Bullman S. Invade seq to study the intratumoural microbiota at host single-cell resolution. Nat Rev Cancer. 2023;23(4):189.

    Article  CAS  PubMed  Google Scholar 

  21. Requena DO, Garcia-Buitrago M. Molecular insights into colorectal carcinoma. Arch Med Res. 2020;51(8):839–44.

    Article  CAS  PubMed  Google Scholar 

  22. Byrd DA, Fan W, Greathouse KL, et al. The intratumor microbiome is associated with microsatellite instability. J Natl Cancer Inst. 2023;115(8):989–93.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhu H, Li M, Bi D, et al. Fusobacterium nucleatum promotes tumor progression in KRAS p. G12D-mutant colorectal cancer by binding to DHX15. Nat Commun. 2024;15(1):1688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Liu W, Zhang X, Xu H, et al. Microbial community heterogeneity within colorectal neoplasia and its correlation with colorectal carcinogenesis. Gastroenterology. 2021;160(7):2395–408.

    Article  CAS  PubMed  Google Scholar 

  25. Geng J, Song Q, Tang X, et al. Co-occurrence of driver and passenger bacteria in human colorectal cancer. Gut Pathog. 2014;6:26.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhu Y, Shi T, Lu X, et al. Fungal-induced glycolysis in macrophages promotes colon cancer by enhancing innate lymphoid cell secretion of IL-22. Embo j. 2021;40(11): e105320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mira-Pascual L, Cabrera-Rubio R, Ocon S, et al. Microbial mucosal colonic shifts associated with the development of colorectal cancer reveal the presence of different bacterial and archaeal biomarkers. J Gastroenterol. 2015;50(2):167–79.

    Article  CAS  PubMed  Google Scholar 

  28. Wu Z, Ma Q, Guo Y, et al. The Role of Fusobacterium nucleatum in Colorectal Cancer Cell Proliferation and Migration. Cancers (Basel). 2022;14(21):5350.

  29. Yamamoto S, Kinugasa H, Hirai M, et al. Heterogeneous distribution of Fusobacterium nucleatum in the progression of colorectal cancer. J Gastroenterol Hepatol. 2021;36(7):1869–76.

    Article  CAS  PubMed  Google Scholar 

  30. Kneis B, Wirtz S, Weber K, et al. Colon Cancer Microbiome Landscaping: Differences in Right- and Left-Sided Colon Cancer and a Tumor Microbiome-Ileal Microbiome Association. Int J Mol Sci. 2023;24(4):3265.

  31. Zhong M, Xiong Y, Ye Z, et al. Microbial community profiling distinguishes left-sided and right-sided colon cancer. Front Cell Infect Microbiol. 2020;10: 498502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nardelli C, Granata I, Nunziato M, et al. 16S rRNA of Mucosal Colon Microbiome and CCL2 Circulating Levels Are Potential Biomarkers in Colorectal Cancer. Int J Mol Sci. 2021;22(19):10747.

  33. Kolisnik T, Sulit AK, Schmeier S, et al. Identifying important microbial and genomic biomarkers for differentiating right- versus left-sided colorectal cancer using random forest models. BMC Cancer. 2023;23(1):647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. De Oliveira AN, Dalmasso G, Nikitina D, et al. The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance. Gut Microbes. 2024;16(1):2320291.

    Article  Google Scholar 

  35. Lee JB, Kim KA, Cho HY, et al. Association between Fusobacterium nucleatum and patient prognosis in metastatic colon cancer. Sci Rep. 2021;11(1):20263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Thomas AM, Jesus EC, Lopes A, et al. Tissue-associated bacterial alterations in rectal carcinoma patients revealed by 16S rRNA community profiling. Front Cell Infect Microbiol. 2016;6:179.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Li Y, Cao H, Fei B, et al. Gut microbiota signatures in tumor, para-cancerous, normal mucosa, and feces in colorectal cancer patients. Front Cell Dev Biol. 2022;10: 916961.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Nakatsu G, Li X, Zhou H, et al. Gut mucosal microbiome across stages of colorectal carcinogenesis. Nat Commun. 2015;6:8727.

    Article  CAS  PubMed  Google Scholar 

  39. Murphy CL, Barrett M, Pellanda P, et al. Mapping the colorectal tumor microbiota. Gut Microbes. 2021;13(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  40. Barot SV, Sangwan N, Nair KG, et al. Distinct intratumoral microbiome of young-onset and average-onset colorectal cancer. EBioMedicine. 2024;100: 104980.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bakar Y, Demiryas S, KıLıNçARSLAN A, et al. The relationship of enterotoxigenic bacteroides fragilis and fusobacterium nucleatum intestinal colonization with colorectal cancer: a case-control study performed with colon biopsies. Mikrobiyol Bul. 2023;57(3):353–64.

    PubMed  Google Scholar 

  42. Fukuoka H, Tourlousse DM, Ohashi A, et al. Elucidating colorectal cancer-associated bacteria through profiling of minimally perturbed tissue-associated microbiota. Front Cell Infect Microbiol. 2023;13:1216024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu Y, Zhao J, Ma Y, et al. The microbiome types of colorectal tissue are potentially associated with the prognosis of patients with colorectal cancer. Front Microbiol. 2023;14:1100873.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358(6369):1443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Warren RL, Freeman DJ, Pleasance S, et al. Co-occurrence of anaerobic bacteria in colorectal carcinomas. Microbiome. 2013;1(1):16.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wang Y, Zhang Y, Qian Y, et al. Alterations in the oral and gut microbiome of colorectal cancer patients and association with host clinical factors. Int J Cancer. 2021;149(4):925–35.

  47. Burns MB, Lynch J, Starr TK, et al. Virulence genes are a signature of the microbiome in the colorectal tumor microenvironment. Genome Med. 2015;7(1):55.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kosumi K, Hamada T, Koh H, et al. The amount of bifidobacterium genus in colorectal carcinoma tissue in relation to tumor characteristics and clinical outcome. Am J Pathol. 2018;188(12):2839–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhu Y, Ma L, Wei W, et al. Metagenomics analysis of cultured mucosal bacteria from colorectal cancer and adjacent normal mucosal tissues. J Med Microbiol. 2022;71(4):10.1099/jmm.0.001523.

  50. Wang X, Jia Y, Wen L, et al. Porphyromonas gingivalis promotes colorectal carcinoma by activating the hematopoietic NLRP3 inflammasome. Cancer Res. 2021;81(10):2745–59.

    Article  CAS  PubMed  Google Scholar 

  51. Lo CH, Wu DC, Jao SW, et al. Enrichment of Prevotella intermedia in human colorectal cancer and its additive effects with Fusobacterium nucleatum on the malignant transformation of colorectal adenomas. J Biomed Sci. 2022;29(1):88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tsoi H, Chu ESH, Zhang X, et al. Peptostreptococcus anaerobius induces intracellular cholesterol biosynthesis in colon cells to induce proliferation and causes dysplasia in mice. Gastroenterology. 2017;152(6):1419–33 e5.

    Article  PubMed  Google Scholar 

  53. Bergsten E, Mestivier D, Donnadieu F, et al. Parvimonas micra, an oral pathobiont associated with colorectal cancer, epigenetically reprograms human colonocytes. Gut Microbes. 2023;15(2):2265138.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Okuda S, Shimada Y, Tajima Y, et al. Profiling of host genetic alterations and intra-tumor microbiomes in colorectal cancer. Comput Struct Biotechnol J. 2021;19:3330–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang X, Yu D, Wu D, et al. Tissue-resident Lachnospiraceae family bacteria protect against colorectal carcinogenesis by promoting tumor immune surveillance. Cell Host Microbe. 2023;31(3):418–32 e8.

    Article  CAS  PubMed  Google Scholar 

  56. Li G, Jin Y, Chen B, et al. Exploring the relationship between the gut mucosal virome and colorectal cancer: characteristics and correlations. Cancers (Basel). 2023;15(14):3555.

    Article  PubMed  Google Scholar 

  57. Uleri E, Piu C, Caocci M, et al. Multiple Signatures of the JC Polyomavirus in Paired Normal and Altered Colorectal Mucosa Indicate a Link with Human Colorectal Cancer, but Not with Cancer Progression. Int J Mol Sci, 2019;20(23):5965.

  58. Nagi K, Gupta I, Jurdi N, et al. Copresence of High-Risk Human Papillomaviruses and Epstein-Barr Virus in Colorectal Cancer: A Tissue Microarray and Molecular Study from Lebanon. Int J Mol Sci. 2021;22(15):8118.

  59. Li X, Wu D, Li Q, et al. Host-microbiota interactions contributing to the heterogeneous tumor microenvironment in colorectal cancer. Physiol Genomics. 2024;56(2):221–34.

    Article  CAS  PubMed  Google Scholar 

  60. Jin M, Shang F, Wu J, et al. Tumor-associated microbiota in proximal and distal colorectal cancer and their relationships with clinical outcomes. Front Microbiol. 2021;12: 727937.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Flemer B, Lynch DB, Brown JM, et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut. 2017;66(4):633–43.

    Article  CAS  PubMed  Google Scholar 

  62. Cao Y, Wang Z, Yan Y, et al. Enterotoxigenic bacteroidesfragilis promotes intestinal inflammation and malignancy by inhibiting exosome-packaged miR-149–3p. Gastroenterology. 2021;161(5):1552–66 e12.

    Article  CAS  PubMed  Google Scholar 

  63. Allen J, Hao S, Sears C L, et al. Epigenetic Changes Induced by Bacteroides fragilis Toxin. Infect Immun. 2019;87(6):e00447–18.

  64. Pleguezuelos-Manzano C, Puschhof J, Rosendahl Huber A, et al. Mutational signature in colorectal cancer caused by genotoxic pks (+) E. coli. Nature. 2020;580(7802):269–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Chen B, Ramazzotti D, Heide T, et al. Contribution of pks (+) E. coli mutations to colorectal carcinogenesis. Nat Commun. 2023;14(1):7827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Dejea CM, Fathi P, Craig JM, et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science. 2018;359(6375):592–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. He Z, Gharaibeh RZ, Newsome RC, et al. Campylobacter jejuni promotes colorectal tumorigenesis through the action of cytolethal distending toxin. Gut. 2019;68(2):289–300.

    Article  CAS  PubMed  Google Scholar 

  68. Mu W, Jia Y, Chen X, et al. Intracellular porphyromonas gingivalis promotes the proliferation of colorectal cancer cells via the MAPK/ERK signaling pathway [J]. Front Cell Infect Microbiol. 2020;10: 584798.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170(3):548–63 e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tang B, Lu X, Tong Y, et al. MicroRNA-31 induced by Fusobacterium nucleatum infection promotes colorectal cancer tumorigenesis. iScience. 2023;26(5):106770.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Qu X, Yin F, Pei M, et al. Modulation of intratumoral fusobacterium nucleatum to enhance sonodynamic therapy for colorectal cancer with reduced phototoxic skin injury. ACS Nano. 2023;17(12):11466–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yan X, Xin Y, Yu Y, et al. Remotely Controllable Supramolecular Nanomedicine for Drug-Resistant Colorectal Cancer Therapy Caused by Fusobacterium nucleatum. Small Methods. 2024;8(3):e2301309.

  73. Ganesan K, Guo S, Fayyaz S, et al. Targeting programmed fusobacterium nucleatum Fap2 for colorectal cancer therapy. Cancers (Basel). 2019;11(10):1592.

  74. Chen L, Zhao R, Kang Z, et al. Delivery of short chain fatty acid butyrate to overcome Fusobacterium nucleatum-induced chemoresistance. J Control Release. 2023;363:43–56.

    Article  CAS  PubMed  Google Scholar 

  75. Li X, Niu J, Deng L, et al. Amphiphilic polymeric nanodrug integrated with superparamagnetic iron oxide nanoparticles for synergistic antibacterial and antitumor therapy of colorectal cancer. Acta Biomater. 2024;173:432–41.

    Article  CAS  PubMed  Google Scholar 

  76. Mishra A, Bharti PS, Rani N, et al. A tale of exosomes and their implication in cancer. Biochim Biophys Acta Rev Cancer. 2023;1878(4): 188908.

    Article  CAS  PubMed  Google Scholar 

  77. Zhang M, Wang Y, Yu L, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis by excretion of miR-122–5p from cells via exosomes. iScience. 2023;26(9):107686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Guo S, Chen J, Chen F, et al. Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16. Gut. 2022;71(2):e1–e3.

  79. Zhang Y, Zhang L, Zheng S, et al. Fusobacterium nucleatum promotes colorectal cancer cells adhesion to endothelial cells and facilitates extravasation and metastasis by inducing ALPK1/NF-κB/ICAM1 axis. Gut Microbes. 2022;14(1):2038852.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-κb, and up-regulating expression of MicroRNA-21. Gastroenterology. 2017;152(4):851–66 e24.

    Article  CAS  PubMed  Google Scholar 

  81. Yu MR, Kim HJ, Park HR. Fusobacterium nucleatum accelerates the progression of colitis-associated colorectal cancer by promoting EMT. Cancers (Basel). 2020;12(10):2728.

    Article  CAS  PubMed  Google Scholar 

  82. Zheng X, Liu R, Zhou C, et al. ANGPTL4-Mediated promotion of glycolysis facilitates the colonization of fusobacterium nucleatum in colorectal cancer. Cancer Res. 2021;81(24):6157–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hong J, Guo F, Lu SY, et al. F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer. Gut. 2021;70(11):2123–37.

    Article  CAS  PubMed  Google Scholar 

  84. Kong C, Yan X, Zhu Y, et al. Fusobacterium nucleatum promotes the development of colorectal cancer by activating a cytochrome P450/Epoxyoctadecenoic acid axis via TLR4/Keap1/NRF2 signaling. Cancer Res. 2021;81(17):4485–98.

    Article  CAS  PubMed  Google Scholar 

  85. Bell HN, Rebernick RJ, Goyert J, et al. Reuterin in the healthy gut microbiome suppresses colorectal cancer growth through altering redox balance. Cancer Cell. 2022;40(2):185-200.e6.

    Article  CAS  PubMed  Google Scholar 

  86. Guo S, Peng Y, Lou Y, et al. Downregulation of the farnesoid X receptor promotes colorectal tumorigenesis by facilitating enterotoxigenic Bacteroides fragilis colonization. Pharmacol Res. 2022;177: 106101.

    Article  CAS  PubMed  Google Scholar 

  87. Zhang S, Yang Y, Weng W, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. J Exp Clin Cancer Res. 2019;38(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Geller LT, Barzily-Rokni M, Danino T, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science. 2017;357(6356):1156–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kordahi MC, Stanaway IB, Avril M, et al. Genomic and functional characterization of a mucosal symbiont involved in early-stage colorectal cancer. Cell Host Microbe. 2021;29(10):1589-98.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang Y, Fu K. Genotoxins: The Mechanistic Links between Escherichia coli and Colorectal Cancer. Cancers (Basel). 2023;15(4):1152.

  91. Cavallucci V, Palucci I, Fidaleo M, et al. Proinflammatory and Cancer-Promoting Pathobiont Fusobacterium nucleatum Directly Targets Colorectal Cancer Stem Cells. Biomolecules. 2022;12(9):1256.

  92. Abdulamir AS, Hafidh RR, Bakar FA. Molecular detection, quantification, and isolation of Streptococcus gallolyticus bacteria colonizing colorectal tumors: inflammation-driven potential of carcinogenesis via IL-1, COX-2, and IL-8. Mol Cancer. 2010;9:249.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Long X, Wong CC, Tong L, et al. Peptostreptococcus anaerobius promotes colorectal carcinogenesis and modulates tumour immunity. Nat Microbiol. 2019;4(12):2319–30.

    Article  PubMed  Google Scholar 

  94. Roelands J, Kuppen PJK, Ahmed EI, et al. An integrated tumor, immune and microbiome atlas of colon cancer. Nat Med. 2023;29(5):1273–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hilmi M, Kamal M, Vacher S, et al. Intratumoral microbiome is driven by metastatic site and associated with immune histopathological parameters: an ancillary study of the SHIVA clinical trial [J]. Eur J Cancer. 2023;183:152–61.

    Article  CAS  PubMed  Google Scholar 

  96. Liu Z, Zhang X, Zhang H, et al. Multi-omics analysis reveals intratumor microbes as immunomodulators in colorectal cancer. Microbiol Spectr. 2023;11(2): e0503822.

    Article  PubMed  Google Scholar 

  97. Borowsky J, Haruki K, Lau MC, et al. Association of Fusobacterium nucleatum with specific T-cell subsets in the colorectal carcinoma microenvironment. Clin Cancer Res. 2021;27(10):2816–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Liu Y, Wong C C, Ding Y, et al. Peptostreptococcus anaerobius mediates anti-PD1 therapy resistance and exacerbates colorectal cancer via myeloid-derived suppressor cells in mice. Nat Microbiol. 2024;9(6):1467–82.

  99. Fong W, Li Q, Ji F, et al. Lactobacillus gallinarum-derived metabolites boost anti-PD1 efficacy in colorectal cancer by inhibiting regulatory T cells through modulating IDO1/Kyn/AHR axis. Gut. 2023;72(12):2272–85.

    Article  CAS  PubMed  Google Scholar 

  100. Overacre-Delgoffe AE, Bumgarner HJ, Cillo AR,et al. Microbiota-specific T follicular helper cells drive tertiary lymphoid structures and anti-tumor immunity against colorectal cancer. Immunity.2021;54(12):2812–2824.e4.

  101. Shi Y, Zheng W, Yang K, et al. Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med. 2020;217(5):e20192282.

  102. Lin Y, Fan L, Qi Y, et al. Bifidobacterium adolescentis induces Decorin (+) macrophages via TLR2 to suppress colorectal carcinogenesis [J]. J Exp Clin Cancer Res. 2023;42(1):172.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Park EM, Chelvanambi M, Bhutiani N, et al. Targeting the gut and tumor microbiota in cancer [J]. Nat Med. 2022;28(4):690–703.

    Article  CAS  PubMed  Google Scholar 

  104. Lacourse KD, Zepeda-Rivera M, Kempchinsky AG, et al. The cancer chemotherapeutic 5-fluorouracil is a potent Fusobacterium nucleatum inhibitor and its activity is modified by intratumoral microbiota [J]. Cell Rep. 2022;41(7): 111625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lehouritis P, Cummins J, Stanton M, et al. Local bacteria affect the efficacy of chemotherapeutic drugs. Sci Rep. 2015;5:14554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sevcikova A, Izoldova N, Stevurkova V, et al. The Impact of the Microbiome on Resistance to Cancer Treatment with Chemotherapeutic Agents and Immunotherapy. Int J Mol Sci. 2022;23(1):488.

  107. Bardelli A, Siena S. Molecular mechanisms of resistance to cetuximab and panitumumab in colorectal cancer. J Clin Oncol. 2010;28(7):1254–61.

    Article  CAS  PubMed  Google Scholar 

  108. Kang X, Liu C, Ding Y, et al. Roseburia intestinalis generated butyrate boosts anti-PD-1 efficacy in colorectal cancer by activating cytotoxic CD8(+) T cells. Gut. 2023;72(11):2112–22.

    Article  CAS  PubMed  Google Scholar 

  109. Li L, He S, Liao B, et al. Orally administrated hydrogel harnessing intratumoral microbiome and microbiota-related immune responses for potentiated colorectal cancer treatment. Research (Wash D C). 2024;7:0364.

    CAS  PubMed  Google Scholar 

  110. Puschhof J, Pleguezuelos-Manzano C, Clevers H. Organoids and organs-on-chips: Insights into human gut-microbe interactions. Cell Host Microbe. 2021;29(6):867–78.

    Article  CAS  PubMed  Google Scholar 

  111. Puschhof J, Pleguezuelos-Manzano C, Martinez-Silgado A, et al. Intestinal organoid cocultures with microbes. Nat Protoc. 2021;16(10):4633–49.

    Article  CAS  PubMed  Google Scholar 

  112. Fu A, Yao B, Dong T, et al. Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer. Cell. 2022;185(8):1356–72 e26.

    Article  CAS  PubMed  Google Scholar 

  113. Zhang J, Hasty J, Zarrinpar A. Live bacterial therapeutics for detection and treatment of colorectal cancer. Nat Rev Gastroenterol Hepatol. 2024;21(5):295–6.

Download references

Acknowledgements

We give a special thanks to Biorender for providing a platform for graphic abstract and Figures 1, 2, 3, and 4. Also thanks to ZYEdit for language help.

Funding

This research was supported by National Natural Science Foundation of China (no: 82205072; Supported by Natural Science Foundation project of Sichuan Science and Technology Department (no: 2024NSFSC1849).

Author information

Authors and Affiliations

  1. TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China

    Jing Long, Jiamei Wang, Chong Xiao, Fengming You, Yifang Jiang & Xueke Li

  2. Oncology Teaching and Research Department, Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China

    Chong Xiao & Xueke Li

  3. Institute of Oncology, Chengdu University of Traditional Chinese Medicine, Chengdu, 610036, China

    Fengming You

Authors
  1. Jing Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jiamei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fengming You
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yifang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xueke Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.G. designed the review protocol, conducted the search, drafted the manuscript, and prepared all Figures and tables. J.M.W. screened potentially eligible studies, extracted and analyzed data, and updated reference lists. X.C. and F.M.Y. were responsible for the funding acquisition. X.K.L. contributed to the design of the review protocol, arbitrating potentially eligible studies, and interpreting results. Y.F.J. and X.K.L. provided feedback on the report. All authors approved the final version of the manuscript.

Corresponding authors

Correspondence to Yifang Jiang or Xueke Li.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Long, J., Wang, J., Xiao, C. et al. Intratumoral microbiota in colorectal cancer: focus on specific distribution and potential mechanisms. Cell Commun Signal 22, 455 (2024). https://doi.org/10.1186/s12964-024-01831-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12964-024-01831-3

Keywords

Cell Communication and Signaling

ISSN: 1478-811X