The most studied examples concern the intestinal microbiota in relation to the occurrence of digestive cancers and particularly colorectal cancer (CRC). In germ-free rats that developed fewer chemically induced colorectal tumors than conventional rats, Weisburger et al. [50] presented the first study associating the gut microbiota with CRC. These findings have been verified in animals prone to CRC [51]. In humans, such a link between gut microbiota and CRC has been reported in several studies (Table 1). In a healthy gut microbiota, the dominant bacteria phyla include Firmucutes, Proteobacteria, Bacteroidetes, and Actinobacteria, with a diverse structure at the genus and species levels in gut micro-communities. To explore the role of gut microbiota in the etiology of cancer, researchers utilize metagenomic analysis that allows comparison of microbiota composition between healthy populations and those with cancer diseases, investigating cancer tissues along with matched healthy tissues.

Contrary to gastric carcinogenesis, which seems to result from a single pathogen [Helicobacter pylori (H. pylori)] [63], the composition of the gut microbiota and more particularly the imbalance between groups of species rather than a particular species seem to be decisive in defining dysbiosis that can generate CRC cancer.

There is little agreement regarding the changes seen in this cancer, despite the fact that many studies have documented dysbiosis in patients with CRC. But several species, like S. bovis, H. pylori, B. fragilis, Enterococcus faecalis (E. faecalis), Clostridium septicum (C. septicum), Fusobacterium spp., and E. coli [64], and more recently Clostridioides difficile, have been specifically considered to have a role in CRC [61].

Overall, gut microbiota diversity decrease seems to be associated with CRC. In contrast to F. nucleatum, which has been linked to disease, Bacteroidetes fragilis acts as a protective factor in the gut by regulating inflammatory immune responses. A major question asked was whether dysbiosis is a risk factor for cancer or whether the tumor is a microenvironment that influences the composition of the microbiota. In fact, it is not to be excluded that in the context of a crosstalk, a dysbiosis makes the bed of cancer which in turn accentuates this imbalance of the microbiota that can participate in the progression of the tumor. To investigate this point, it is interesting to know if dysbiosis is associated with the presentation of cancer.

Investigations into the association of gut microbiota dysbiosis with CRC were carried out considering mostly the stage, the grade of the disease, the CpG methylation, and instability of microsatellite profiles, these latter being associated with colorectal carcinogenesis pathway. The case for differences in gut microbiota composition by stage of CRC has been provided by several researchers. It seems that there are microbial metacommunities that change according to the progression of the cancer. According to one study, it is possible to anticipate the shape and function of certain mucosal microbial communities as colorectal neoplasms develop along the adenoma-carcinoma sequence [65]. However, two man species have been particularly associated with the presentation of CRC. Some researches suggest that E. coli may contribute to the pathophysiology of CRC. A connection between the tumor-node-metastasis stage and E. coli colonization of the mucosa was specifically noted. In addition, it has been shown that pathogenic cyclomodulin-positive E. coli bacteria were more common in the mucosa of individuals with stage III/IV colon cancer than in stage I colon cancer patients. The correlation between the tumor proliferative index and E. coli colonization of the mucosa was also significant [66].

Another study that demonstrated that advanced colorectal neoplasia patients’ large intestine mucosa is colonized with more virulent strains of E. coli and that higher bacteriocin production was associated with an increasing stage of CRC [assessed according to tumor, nodes and metastases (TNM) classification], supported these findings [67]. Other species were also involved in the progression and aggressiveness of CRC. Fusobacterium and also ETBF showed important associations with CRC clinicopathological features. Fusobacterium has been particularly involved in such features. Increased levels of F. nucleatum were shown to be related to CRC progression and to CRC patient survival [68]. Fusobacterium spp. levels were significantly greater in late stage (III/IV) colorectal malignancies, and an excess of F. nucleatum has been linked to a higher risk of lymph node metastases in colon cancer [68]. Regardless of the histology, F. nucleatum was discovered in premalignant colorectal lesions, however, it was more frequently found in lesions with high CpG island methylator phenotype (CIMP) levels. Additionally, F. nucleatum increased with histological grade, indicating that it might aid in the development of colorectal neoplasia. The hypothesis of the “colorectal continuum” may be supported by the presence of F. nucleatum positive in CR tumors [69]. Furthermore, mounting data suggests that F. nucleatum may contribute to particular molecular subgroups of CRCs, including the CIMP and microsatellite instability (MSI) [70].

The pathogenesis of colon, gastric, esophageal, pancreatic, laryngeal, breast, lung, and gallbladder carcinomas has been linked to gut microbial dysbiosis. This change appears to be intimately related to the host inflammation brought on by microbial dysbiosis. We will present some here the cases of lung and breast cancers (BCs) which are the most frequent around the world.

In contrast to the control group, lung cancer patients had a much lower relative abundance of several gut microorganisms. These results imply that there may be some indirect links between lung cancer and gut microbiome [71]. Lung and intestinal flora have an impact on how lung cancer develops, is treated, and is prognosed. These factors will help develop new lung cancer prevention, detection, and treatment methods [72].

BC and gut microbial dysbiosis have been linked in several studies. As compared to healthy women, the microbiota of BC patients is different, suggesting that specific bacteria may contribute to the development of the disease. Elevated serum levels of estrogen can be modified by the gut flora. Contrarily, chemicals that resemble estrogen may encourage the growth of specific bacterial species. As a result, there may be a synergistic effect between the microbiota and both endogenous hormones and estrogen-like substances that raise the chance of developing hormone-related disorders like BC [73]. According to other research, breast tissue has a unique microbiome, with some species being elevated in the breast tissue itself as well as the gut bacteria of BC patients. More significantly, the microbiome of the breast and its associated tissues may act as potential indicators for detecting and staging BC [74]. It has been hypothesized that BC development may be influenced by changes in the mammary and intestinal microbiota. Bacteria from the phyla Proteobacteria, Firmicutes, Actinobacteria, and Lactococcus spp. are abundant in healthy breast tissue and may therefore have potential preventive effects against BC. But in malignant mammary tissues, some bacteria are more prevalent. The dysbiosis of the gut microbiota, on the other hand, has been associated with BC because some gut bacteria can affect the synthesis of advantageous metabolites and interfere with the metabolism of estrogen in the stomach. Such surprising connections between BC and gut microbiota in the breast and BC suggest potential solutions for managing BC, such as through the use of probiotics, both in terms of prevention and management [75]. It has been established that the compositional abundance of some bacterial families and the synthesis of microbial metabolites vary in BC. It might be said that microbial dysbiosis appears to be linked to the development of BC [76].

Instability in the genome and the proliferation of epithelial cells are two factors in the development of CRC that are brought on by these mechanisms, which also have a variety of cellular effects and affect the host’s defenses. The dysbiotic bacteria implicated in cancer initiation produce toxic molecules that can induce DNA damage leading to transformation. Cyclomodulins are bacteria toxins that can induce DNA damage, interfere with the cell cycle, and/or apoptosis. Among such toxins, cytolethal distending toxin (CDT) and colibactin can directly damage DNA and induce genomic instability. Considered true genotoxins they are able to provoke double-strand DNA breaks [78, 79].

Oxidative stress could be another mechanism involved in carcinogenesis. Highly reactive molecules called reactive oxygen species (ROS) are created from oxygen. According to research, ROS induction plays a crucial part in CRC that is connected to the microbiome. Because hydroxyl radicals are potent mutagens that may cause DNA breaks, point mutations, and protein-DNA crosslinking, enterococci species, particularly E. faecalis, can produce them [80], which can contribute to genomic instability in CRC [81, 82]. The gut microbiota also promotes host-derived production of nitric oxide and its secondary nitric oxide synthases (NOS), which can induce DNA damage. Some bacterial species such as Lactobacilli and Bifidobacteria can directly generate NOS [83]. Some enteropathogenic E. coli strains have the potential to downregulate the DNA measles, mumps, and rubella (MMR) system, demonstrating the connection between oxidative stress and DNA repair mechanisms [84]. The accumulation of mutations linked to the development of CRC can result from this downregulation of the MMR repair mechanism [85]. Viljoen et al. [54] also noted that F. nucleatum colonization was more prevalent in the colon of CRC patients who had a phenotype associated with MSI caused by MMR deficiency.

These findings support the theory that the gut bacteria and DNA repair mechanism interact to cause CRC.

The dysbiotic bacteria implicated in cancer produce toxic molecules that interfere with proliferation and apoptosis signaling pathways leading to cell transformation. Some bacteria toxins may be involved in colorectal carcinogenesis through the activation of carcinogenesis-promoting pathways. The examples of cytotoxin-associated gene A (CagA) or vacuolating cytotoxin gene A (VacA) produced by some H. pylori strains are well known [86]. Through direct binding, phosphorylation of signaling proteins, and methylation of tumor suppressor genes, CagA impacts the expression or function of critical proteins in oncogenic or tumor suppressor signaling pathways [87, 88]. VacA activates the signaling pathway of the mitogen-activated protein kinases (MAPK) p38, and extracellular signal-related kinases 1 and 2 (ERK1/2). Moreover, VacA activates a signaling pathway involving G-protein-coupled receptor kinase-interactor-1 (Git1) leading to the upregulation of the β-catenin signaling pathway involved in CRC [89].

The B. fragilis toxin (BFT) is one more illustration of a bacterial toxin that contributes to the development of CRC. In order to activate the Wnt and nuclear factor-kappa B (NF-κB) pathways, the zinc-dependent metalloprotease toxin BFT must attach to a particular colonic epithelial receptor. These outcomes result in accelerated cell division, epithelial release of pro-inflammatory mediators, and development of DNA damage [90, 91].

As widely demonstrated, the microenvironment plays a determining role in the promotion of tumors and the progression of cancer. According to the theory of the carcinogenic effect of the dysbiotic microbial community, dysbiosis could be sufficient to promote cancer, suggesting that the microbial environment of the tumor should play an important role in its progression.

Among the described mechanisms, it is necessary to consider inflammation and host immune defenses modulation, as key factors in the interactions between the gut microbiota and CRC. It is now widely accepted that people with inflammatory bowel illness have a higher chance of getting CRC. Since their microbiota underwent significant alterations throughout the development of CRC, inflammation may be a result of the host’s reaction to those changes [92, 93]. One of the microorganisms most closely linked to inflammatory bowel illness is E. coli. In individuals with inflammatory bowel illness, it has been seen that adherent and invasive E. coli abnormally colonize the gut mucosa. The bacterial control of inflammation in colorectal carcinogenesis is supported by the ability of CRC-associated E. coli to promote the expression of the pro-inflammatory gene cyclooxygenase-2 (COX-2) in macrophages [94, 95]. The gut microbiota participates in metabolic processes, and it is acknowledged that CRC development is significantly influenced by microbial-derived metabolism [96]. By controlling the production of secondary bile acids, the metabolic activation of carcinogenic substances, dietary phytochemicals, and xenobiotics, hormone metabolism, and the regulation of inflammatory pathways, these metabolic activities may influence colorectal carcinogenesis [97].

Intestinal epithelial cell differentiation and proliferation, energy storage from food sources, vitamin synthesis, ion absorption, and mucus formation are all potential outcomes of these processes [98].

Mucosal tumors are in direct contact with bacteria and therefore are susceptible to influence from the microbiome. In the gut, CRC is exposed to various bacterial species that’s why it has been extensively studied. Interestingly, the tumor tissue microbiome is not fully consistent with the composition of the fecal microbiota [62]. In CRC tissues, Fusobacteria and Firmicutes are increased, while the abundance of taxa including Fusobacteria, Providencia, and Actinobacteria are altered between cancerous and adjacent normal tissue [111, 55]. In numerous studies, the presence of these bacteria in colonic tumor tissues is associated with histologic grade, T cell infiltration, resistance to chemotherapy, and poorer overall survival [112–114]. In colonic tumors, F. nucleatum has been reported to be enriched and it is likely to have translocated from feces in the gut into colonic epithelium, inducing proinflammatory and oncogenic pathways [115, 116]. It expresses an adhesion protein called FadA, which can bond to E-cadherin and permit the bacteria to invade CRC cells, causing β-catenin regulated transcription of the oncogenes myelocytomatosis oncogene (Myc) and Cyclin D1, and increased cancer cell proliferation [115, 116]. In mouse models, F. nucleatum has been shown to induce colorectal tumor via the microRNA (miRNA)—miR21, inhibitors of which prevented CRC cell line proliferation and invasion [116]. miRNAs have been shown different expressions between normal and tumoral colonic tissues, and have been correlated with the microbiome profile of the colon, providing another mechanism by which the gut epithelium can interact with bacteria [115].

Gut microbiota dysbiosis has been long related to decreases in butyrate production within several cancer types, therefore, decreases in butyrate may cause a leakiness of the intestinal epithelium which allows bacteria to migrate to distant tissues via the vasculature [117]. Bacteria have been found in distant tumoral tissues of the intestine such as biliary, esophageal, breast, and cervical cancer, although their significance remains unclear [118, 119]. A recent study analyzing seven human tumor types disclosed a specific microbiome composition in each, and that most bacteria were localized intracellularly within cancer and immune cells of the TME [120]. These findings point out a strong physical relationship between microorganisms and cancer cells at a local level. In agreement with this, human CRC shows the same microbiome composition with its metastatic lesions in the liver, suggesting that the microbiome is able to travel with the primary tumor cells to distant sites [120]. Recently, intratumoral CRC-associated E. coli was shown to enter the liver after gut vascular barrier disruption. Once in the liver, E. coli were reported to prime the liver microenvironment through the recruitment of innate and inflammatory immune cells to directly promote metastasis [121]. Furthermore, oncogenic bacteria ascendant from the cervix were reported able to reach and colonize the uterus and ovaries during carcinogenesis [122]. In a recent study, Klebsiella pneumoniae and some common denominators (Enterobacter cloacae, Citrobacter freundii, and Fusobacterium) were linked with pancreatic cancer as well as BC [120]. These cancer-associated microbes were found to reach the pancreas via peri-intestinal translocation through the pancreatic duct due to gut epithelial barrier damage [123]. Moreover, long-term pancreatic ductal adenocarcinoma survivors had higher intratumoral bacterial diversity and the microbiome signature was significantly different from that of short-term survivors [13]. Interestingly, three enriched genera were identified in long-term survivors (Saccharopolyspora, Pseudoxanthomonas, and Streptomyces), which had a positive correlation with the number of CD8⁺ T cells, suggesting their role in the antitumoral immune response [13]. Functionally, the connections between gut microbiota and intratumoral microbes of the TME are only beginning to be explored and merit further mechanistic investigation.

Papillomaviridae is a family of non-enveloped viruses with double-stranded DNA genomes [132]. The human infection member human papillomaviruses (HPV) has been associated with several types of cancer, most notably cervical cancer [127]. However, only a fraction of the approximately 150 HPV types, the so-called high-risk types such as HPV-16 and -18, are commonly associated with cancer [133]. The main mechanisms for the contribution of high-risk HPV to cervical cancer are the integration of viral DNA into the host genome and the expression of viral oncogenes. For example, the early oncogenes E6 and E7 have been shown to degrade the tumor suppressor gene p53 and the retinoblastoma protein (pRb), inter alia, causing cells to arrest in S phase, leading to genomic instability, aneuploidy, and DNA damage, and thus carcinogenesis [134]. Similar mechanisms are thought to operate in other HPV-associated cancers such as CRC [135]. In addition, E7 has been reported to induce angiogenesis [136], and E6 and E7 also deregulate cellular energy. E7 leads to the Warburg effect, a shift from standard oxidative phosphorylation-based metabolism to aerobic fermentation [137], and E6 proteins prolong activation of mammalian target of rapamycin complex 1 (mTORC1) signaling by inhibiting receptor protein tyrosine kinase signaling, making cells “blissfully ignorant” regarding their energy state [138].

Viruses of the Herpesviridae family are enveloped in double standard DNA (dsDNA). Various members such as cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex virus 1/2 (HSV1/2) and HSV6 and HSV7 have been implicated in cancer formation [128, 139, 140]. The strongest association with cancer has been reported for EBV, which has been linked to several cancer types including colorectal [141], esophageal [142], and gastric cancer [142]. EBV is an oncogenic γ-1 herpesvirus associated with a variety of lymphoid malignancies, including a variety of B cell, T cell, and natural killer cell (NK cell) lymphomas and epithelial carcinomas [143]. EBV mimics B cell proliferation and survival signals, enabling it to replicate its genome while remaining latent and immunosilent in host B cells, creating a lifelong persistence that favors its spread [143]. When EBV first infects naive B cells, it adopts a growth program or Late III (Lat III) pattern, and EBV expresses Epstein-Barr nuclear antigen 1 (EBNA1)–EBNA6 as well as latent membrane protein 1 (LMP1), LMP2A, and LMP2B. This expression pattern forces infected cells to become proliferating B cells, allowing EBV episomes to replicate [143].

Recently, more and more evidences have shown that GI cancer can lead to the occurrence and development of cancer, especially GI cancer. Metagenomic analysis of stool samples from patients with CRC revealed a characteristic fecal fibroma, indicating increased abundance and diversity of intestinal fibroids [144]. Enteroviral markers that distinguish CRC from non-CRC controls include orthobuniaviruses, tunalikeviruses, phikzlikeviruses, and other viral genera [144]. Phage enrichment has been demonstrated for inoviruses and tunalikeviruses [144], reported, certain species of inoviruses can regulate the production of bacterial biofilms that contribute to colon carcinogenesis [145] and significantly reduced Enterobacteriaceae phages and crAssphage compared to healthy controls [146]. With regard to eukaryotic viruses, especially human oncogenic viruses, EBV, HPV, human polyomavirus, and CMV showed higher prevalence in CRC tissues compared with non-CRC tissues [147]. Preliminary evidences also suggest that EBV infection may contribute to the development of CRC by inducing mutations in enterocytes [148]. It has been reported that EBV-infected B lymphocytes produce microvesicles containing EBV-derived molecules that translocate to intestinal epithelial cells and subsequently initiate oncogenic transformation [149]. Polyomaviruses have been reported to produce T antigens and inactivate important regulatory tumor suppressor proteins, thereby inducing chromosomal instability and malignant transformation of colonocytes [149].

The mechanism by which commensal or pathogenic bacteria transcend the gut barrier into the tumoral milieu, where they might increase the side effects of chemotherapy [151], was first documented in the 1960s [152]. In addition, the microbiota can modulate the chemotherapeutic response by modifying the immune response. In fact, it has been demonstrated that the continual interaction of the innate and adaptive immune systems with the gut microbiota at the mucosal surface controls inflammation and sets the immunological tone [153]. However, it has been shown that chemotherapy medications harm the mucosal epithelium, which results in bacterial translocation. This might cause a systemic infection, increasing the host’s exposure to various pathogens and priming the adaptive immune system to respond more favorably to chemotherapy [81, 82]. Immunomodulation can occur by several mechanisms. The most studied mechanisms are bacterial translocation and TH17 cell activation that enhances the action of cyclophosphamide (CTX); the activation of intraluminal myeloid cells that increases oxaliplatin action and microbiota-induced T cell activation can facilitate novel anticancer immunotherapy [154].

Numerous immunological mechanisms have been implicated in the anti-neoplastic actions of the widely used alkylating drug CTX [82, 84]. Using a mouse sarcoma model, research by Viaud et al. [155] revealed that both doxorubicin and CTX shorten intestinal villi and disrupt the intestinal barrier, causing commensal bacteria to translocate into secondary lymphoid organs. They have demonstrated that CTX can change the microbiota of the small intestine, causing bacterial species from the Firmicutes phylum, such as Roseburia, Coprococcus, and unclassified Lachnospiraaceae, as well as Lactobacilli and Enterococci, to become less prevalent [156]. Additionally, recent studies reported that a corrupted microbial barrier was more permeable to Gram-positive bacteria leading to the translocation of Lactobacillus johnsonii, Lactobacillus murinus, and Enterococcus hirae (E. hirae) from the gut into the lymphoid organs [157]. Translocated bacteria promote TH17 cell development once they reach the spleen and mesenteric lymph nodes, leading to an antitumor adaptive immune response. Recent studies have shown that vancomycin-pretreated mice had less Th17 cells in their spleens than untreated animals, and they have indicated that adoptively transferring pathogenic Th17 cells to the treated mice may restore a therapeutic response [158]. Additionally, a recent clinical study has shown that a memory Th1 immune response to E. hirae among patients with end-stage lung and ovarian cancer was proven to be a favorable predictor of progression-free survival [82, 85, 159].

Furthermore, Iida et al. [160] have investigated the impact of microbiota and myeloid cell interaction on chemotherapeutic efficacy in a murine lymphoma model. They have demonstrated that pre-treatment of mice with subcutaneous EL4 lymphoma with antibiotics could reduce both DNA damage caused by oxaliplatin and the expression of genes responsible for ROS generation by myeloid cells [161]. It leads to the conclusion that a healthy microbiota may boost the antitumor impact of oxaliplatin by prepping myeloid cells for ROS release, improving inflammatory cytokine production, and ultimately eradicating tumors [161].

The gut microbiota seems to have the potential to directly metabolize chemotherapeutic drugs and indirectly alter host-chemotherapeutic metabolism by modifying the host metabolic milieu [86, 88]. The gut microbiota seems to have the potential to directly metabolism chemotherapeutic drugs and indirectly alter host-chemotherapeutic metabolism by modifying the host metabolic milieu [86, 88]. Recent studies show that changes in the gut microbiota may be the cause of the varying clinical response to fluoropyrimidines, using the Caenorhabditis elegans (C. elegans) nematode worm as a model for symbiotic host-microbial interactions [161]. García-González et al. [162] tested the impact of either E. coli or Comamonas bacteria administration in the efficacy of camptothecin (CPT), 5-fluorouracil (5-FU), and 5-fluoro-2’-deoxyuridine (FUDR) in C. elegans. The gut microbiota seems to have the potential to directly metabolism chemotherapeutic drugs and indirectly alter host-chemotherapeutic metabolism by modifying the host metabolic milieu [86, 88]. It was found that the response to chemotherapeutic was affected by bacterial species differently. In fact, C. elegans fed by E. coli was more sensitive to the sterilizing effect of FUDR [161].

Further investigations suggested that microbial metabolism of anticancer drugs could cause severe side effects such as diarrhea, pain, and weight loss leading to dose limitation, which reduces the efficacy of anticancer treatment. Recent studies have demonstrated that irinotecan induced diarrhea in up to 30% of patients requiring dose reduction and, in many cases, the immediate termination of the drug [162]. Irinotecan (SN-38), an inhibitor of topoisomerase 1, is inactive after being subjected to hepatic glucuronidation, which results in SN-38G, which is subsequently eliminated by bile. However once in the gut lumen, SN-38G is reactivated to SN-38 by the bacterial β-glucuronidases. According to recent research, β-glucuronidase-producing bacteria including Faecalibacterium prausnitzii and Clostridium spp. contribute to the gut’s buildup of the active irinotecan metabolite (SN-38) [163].

Intestinal health and symbiosis between the host and microbiota are both maintained in large part by the composition of the bacterial community [25]. It has been reported that the microbial community is reciprocally modified by anticancer drugs. Anaerobes and streptococci were both absolute and relative microbial abundance decreasers, whereas Bacteroides were relative microbial abundance increasers, according to a research done on rats given methotrexate. Reduced villous length and diarrhea were linked to this alteration in microbial composition [164]. Additionally, a clinical study on 28 non-Hodgkin lymphoma patients who received a 5-day myeloablative chemotherapy regimen revealed profound changes in the gut microbial community’s structure and reduction of its diversity, as well as an increase in the abundance of Proteobacteria and a decrease in Firmicutes and Actinobacteria [165]. After chemotherapy, there was a decrease in taxa that have been demonstrated to suppress inflammation by altering the NF-κB pathway and by producing SCFAs. Further studies revealed a negative correlation between the quantity of Firmicutes and several metabolic pathways linked to intestinal inflammation, including cell motility, glycan metabolism, and xenobiotic degradation [165].

Ipilimumab is a monoclonal antibody that works by blocking CTLA-4, mainly used for the treatment of metastatic melanoma [178]. Emergent data from preclinical studies showed that the efficacy of ipilimumab treatment is affected by gut microbiota modulation and depends particularly on distinct Bacteroides species [179]. In fact, in germ-free and antibiotics-treated mice, the response to anti-CTLA-4 treatment was compromised [180]. Besides, the efficacy of CTLA-4 blockade was restored in these in vivo models after gavage with B. fragilis, where animals responded the best to ipilimumab treatment, and the size of the tumors was negatively correlated with the outgrowth of B. fragilis [181]. It has been hypothesized that B. fragilis boosts Th1 immune response in lymph nodes that is dependent on interleukin-12 (IL-12) and encourages intratumorous DC maturation, restoring their responsiveness to CTLA-4 inhibition [182]. In other key clinical studies that strongly support the inclusion of microbial targeting in anti-tumor immunotherapy efficacy and complementing the animal models, similar observation has been reported in a good responder group of patients treated with ipilimumab [183]. The analysis of stool samples among this group showed a selective enrichment of B. fragilis [183]. In the same context, other species, like Bifidobacterium breve and Bifidobacterium longum have been correlated to the activation of immune cells in the TME during ipilimumab therapy [184].

Similarly, the clinical response to the antitumor monoclonal antibodies against-PD-1 or its ligand PD-L1 was shown to have a direct link with microbiome signature [185]. A recent animal study showed improved efficacy of the anti-PD-1/PD-L1 treatment in germ-free mice transplanted with fecal microbiota from good or poor responders and supplemented with Clostridiales and Faecalibacterium species [186]. Another report has demonstrated that the addition of Akkermansia muciniphila, Alistipes indistinctus, or E. hirae could invigorate the immunotherapy treatment in germ-free mice [187, 188]. Accordingly, a metagenomic analysis showed that the enrichment of Akkermansia muciniphila in faecal samples from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients were related to a promising clinical outcome during anti-PD-1 and anti-PD-L1 therapies [189]. Further, a high level of commensal bacteria in patients with melanoma was correlated with enhanced antitumor immune response. One suggested mechanism to explain the improvement of immunotherapy treatment is an increase in intratumoral infiltration of CD8⁺ T cells with enhanced tumor-specific T cell and DC-mediated immune responses [190]. On the other hand, the reduced response or the resistance to PD-1/PD-L1 immunotherapy has been associated with a high abundance of Bacteroidales [191]. Nevertheless, numerous studies pointed out the impact of antibiotics to engender dysbiosis that subsequently compromise the anti-PD-1 efficacy in cancer patients [192]. For instance, across the different cohort studies related to the anti-PD-1 or PD-L1 therapies, an overlap in the involved microbiota species has been raised. The heterogeneity of cancer types, the tumor’s microenvironment, the host genetic background and immune system, or even the sequencing approaches, may lead to biases [192]. It seems likely that a microbial responder profile reflects a combination of key species instead of a separate one.

When considered collectively, those results strongly imply that a balance between “useful” and “non-beneficial” bacteria may be able to influence the effectiveness of both immunotherapy and chemotherapeutic treatments. An anticancer medication has the potential to change the gut microbiota’s composition and the supplementation of beneficial bacterial strains may lead to better efficacy and response of the anticancer therapy.