The etiology of cancer is characterized by multiple factors, encompassing: (1) genetic influences, involving hereditary elements linked to inherited genetic predispositions, such as specific mutations, locus weakening, deletions, activation of proto-oncogenes, and inactivation of tumor suppressor genes; (2) external factors, encompassing exposure to carcinogens or procarcinogens; (3) internal factors, associated with the metabolism of procarcinogens into carcinogens, modifications in the local microenvironment, stress conditions leading to the production of reactive oxygen species, and compromised or abnormal functioning of the immune system; and (4) microbial factors, particularly in instances where the microbiota undergoes alterations (dysbiosis) and becomes enriched with microorganisms producing genotoxic compounds.

The gut microbiome has been recognized as an important player in cancer development and progression (1).

Microbiota, comprising bacteria, fungi, microalgae, or protozoa, along with viruses, have the potential to instigate or advance neoplastic processes. This can occur through the direct synthesis of carcinogenic compounds, exerting genotoxic effects, direct inactivation of genes, initiation of local inflammatory processes leading to alterations in the local microenvironment, or impairment of the immune system’s functionality, resulting in immunosuppression. Recent developments also indicate that the microbiome holds an important role in modulating the efficacy and toxicity of chemotherapeutic drugs (irinotecan, 5-fluorouracil, oxaliplatin, cyclophosphamide, gemcitabine, methotrexate) and immunotherapeutic compounds (anti-cytotoxic T-lymphocyte-associated antigen 4, anti-programmed death-ligand 1/anti-programmed cell death protein 1) (2, 3). Oncologic outcomes are highly impacted by the microbiome composition and functions, hence there is an imperative need to develop personalized treatment approaches targeting the microbiota.

Within this line of thought, this review aims to present the influence of the gut microbiota in antitumoral therapies, and the ways of modulating the microbiome in cancer treatment.

The gut microbiota has long been known to play an important role in maintaining health and triggering disease, with increasing evidence recently also accumulating on its positive involvement in modulating the effectiveness of chemotherapy and immunotherapy (55). On the other hand, there are studies showing that ablation of the gut microbiota by antibiotics reduces the efficacy of some cancer treatments (56). The mechanisms by which the microbiota promotes positive response to treatment are not fully known, but various studies in the field suggest that they include epigenetic regulation of gene expression, modulation of immune response, enzymatic degradation and drug metabolism (55).

Administered in low doses, cyclophosphamide (CTX), an alkylating agent with antiangiogenic and immunostimulatory effects, causes translocation of Gram-positive intestinal bacteria, such as Enterococcus hirae, to secondary lymphoid organs, stimulating intratumorally increase in the TCD8+/TCD4+ ratio (56) and differentiation of CD4+ T helper 17 (Th17) lymphocytes. Th17 lymphocytes induce an inflammatory reaction in tumor tissues that increases the tumoricidal effect of CTX (57). On the other hand, during CTX treatment, Barnesiella intestinihominis accumulates in the colon and promotes infiltration of Tγδ lymphocytes into tumor lesions, where they produce IFN gamma (56). These effects do not occur in germ-free mice, which easily acquire resistance to CTX (57).

CpG oligonucleotides are used in cancer immunotherapy. They form a complex with the TLR9 receptor (Toll-like receptor 9) and activate macrophages, monocytes, dendritic cells, NK cells and B and T lymphocytes, fostering the synthesis of INF alpha (58). The intestinal microorganisms, in particular Ruminococcus sp. and Alistipes shahii, are positively correlated with TNF and granzyme B secretion and play an important role in triggering an antitumor immune response (23).

Oxaliplatin is a new-generation chemotherapeutic agent used in the first-line treatment of many cancers, including skin and advanced cancers of the appendix, colon and rectum. Its mechanism of action is based on the delivery of platinum ions into the nuclei of tumor cells, where they form adducts with genetic material, block replication and cause cell death (59). Oxaliplatin has lower toxicity and higher efficacy than previous similar drugs (cisplatin, carboplatin) and, unlike them, induces immunogenic cell death and promotes anti-tumor T-lymphocyte immunity. Administered to laboratory animals with intact gut microbiota, oxaliplatin destroys subcutaneous EL4 tumors and prolongs survival, an activity greatly diminished in previously antibiotic-treated animals. Finally, germ-free animals did not respond to oxaliplatin treatment (60). Among the microorganisms that contribute to oxaliplatin efficacy are Bacteroides fragilis, which stimulates infiltration of CD8+ cytotoxic T lymphocytes into the tumor microenvironment (61), and microorganisms of the genera Ruminococcus, Clostridium (Clostridium butyricum), Eubacterium (Eubacterium hallii and Eubacterium rectale), Coprococcus, Faecalibacterium, Butyrivibrio etc., which produce butyric acid (62). This is a short-chain fatty acid that, in low concentration, enhances the activity of tumor-infiltrating CD8+ cytotoxic T lymphocytes and, in synergy with the probiotic Bifidobacterium bifidum, causes increased production of granzyme B (63).

Fluoropyrimidines are fluorinated derivatives of uracil and are used as antimetabolites in the treatment of several types of cancers to induce DNA breaks, disruption of DNA replication and RNA synthesis, and ultimately cell death (64, 65). These drugs, such as intravenously administered 5-fluorouracil (5-FU) and orally administered capecitabine, are predominantly converted in tumor cells and liver to the cytotoxic 5-fluorouracil form of thymidine phosphorylase. In the presence of 5-fluorouracil, Lactobacillus acidophilus CL1285 and Lactobacillus casei LBC80R strains induce apoptosis of LS513 human colorectal cancer cells (66), and in HER2-negative metastatic breast cancer, the abundance of microorganisms such as Slackia and Blautia obeum is associated with progression-free survival (67).

CTLA4 inhibitors are a group of drugs designed to block CTLA4 (cytotoxic T-lymphocyte-associated protein 4)/CD152 (cluster of differentiation 152) activity. This receptor is expressed on the surface of regulatory T lymphocytes and, by binding to B7.1 (CD80) protein expressed by cytotoxic T lymphocytes, attenuates their activity (22). Therapeutic blockade of CTLA4 is achieved with immune inhibitors of CTLA4, such as the antibody ipilimumab, which can restore anti-tumor activity to cytotoxic T lymphocytes. Administration of ipilimumab induces intestinal dysbiosis, marked by multiplication of bacteria of the Clostridiales genera and reduction of those of the Bacteroidales and Burkholderiales genera, while the colony density of Bacteroides fragilis appears to be unaffected by it (22). Moreover, the high density of Bacteroides fragilis stimulated by ipilimumab (23, 25)] is associated with reduced tumor volume. Enterococcus faecium induces synergistic antitumor effects of CTLA4 inhibitors via peptidoglycan fragments, which activate CX3CR1+ monocytes, stimulate cytotoxic lymphocytes to produce granzyme B, and reduce the number of tumor-associated macrophages (23).

PD1 (Programmed cell death 1) and PDL1 (Programmed cell death ligand 1) inhibitors, are immunosuppressors of T lymphocytes, impair their function and promote tumor proliferation and invasiveness (68), and their antagonists are used in the treatment of cancers, including the anti-PD1-directed monoclonal antibody products nivolumab, pembrolizumab and durvalumab, and the anti-PDL1-directed atezolizumab and avelumab (69), which specifically target and destroy tumor cells. The presence of some bacterial species in the gut of people with cancer may amplify the immune response of PD1- and PDL1-directed products and prolong their survival. Thus, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium breve, Bifidobacterium pseudolongum, Akkermansia muciniphila ATCC BAA-835 and Faecalibacterium prausnitzii enhance the activity of anti-PD1 antibodies (22, 23). Enterococcus faecium has synergistic action with PD1 inhibitors and PDL1 inhibitors via peptidoglycan fragments (23), and Faecalibacterium sp. appears to be associated with anti-PDL1 response (70).

The presence of Escherichia coli, Listeria welshimeri, Bifidobacterium breve, Lactococcus lactis and Lactobacillus sp. in the gastrointestinal tract of people with lung or prostate carcinomas has a synergistic effect with some antitumor drugs. Thus, Escherichia coli is associated with enhanced activity of tretazicar (CB1954), fludarabine phosphate, 5-fluorocytosine, 6-mercaptopurine-2-deoxyriboside and gemcitabine, Listeria welshimeri with that of fludarabine phosphate and tretazicar (CB1954) (71), Bifidobacterium breve and Lactococcus lactis with that of tretazicar (CB1954), and Lactobacillus sp., with that of 5-fluorocytosine (72).

Probiotics are cultures of living microbial cells that colonize and benefit the human body. They naturally define the state of eubiosis and can be affected by antibiotic use, different diets and infections with different pathogens. Among the diets that favor their development are those containing prebiotics, oligosaccharides or other non-digestible, fermentable compounds that modify the structure and/or activity of the gut microbiota, with beneficial effects on health. Of these, only fructo-oligosaccharides and galacto-oligosaccharides are generally considered safe, while a wider range of prebiotics, including pectin oligosaccharides, xylo-oligosaccharides, isomalto-oligosaccharides, gluco-oligosaccharides, mannan-oligosaccharides, gentio-oligosaccharides, soybean oligosaccharides, chito-oligosaccharides and polydextrose are still being evaluated for safety, and the number of prebiotics that will become safe may increase in the future (73).

Gut colonization with probiotics, including bacteria Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis and Bacillus cereus, inhibits the growth of pathogenic microorganisms, including Desulfovibrio, Mucispirillum and Odoribacter, helping to reduce the risk of colon cancer and associated colitis, and the probiotic yeast Saccharomyces boulardii inhibits Bacillota, Proteobacteria and Tenericutes, promotes the growth of Bacteroidetes, with metabolic modification, and is indicated in the treatment of obesity and type 2 diabetes (74). Probiotics regulate intestinal transit, restore and maintain gut microbiota after antibiotic treatment, reduce intestinal inflammation, secrete butyric acid and propionic acid (short-chain fatty acids) and may contribute to the reduction of tumor volume and number/volume of metastases, acting synergistically with anti-tumor drugs (75, 76). In murine melanoma, short-chain fatty acids synthesized in the intestine and transported via the bloodstream stimulate CCL20 (C-C Motif Chemokine Ligand 20) expression in endothelial cells in lung metastases, recruitment of Th17 lymphocytes, and reduction in the number of lung metastases (77). In experiments on human intestinal Caco-2 cells whose tight junctions were disrupted to reconstitute conditions in small intestinal necrotizing colitis, the probiotics Lactobacillus rhamnosus and Lactobacillus plantarum restored these junctions, with the cluster of cells regaining intestinal barrier function (78). In murine breast cancer, administration of milk fermented with Lactobacillus casei CRL431 reduces the secretion of the pro-angiogenic cytokine IL6, and similarly Lactobacillus reuteri isolated from human milk increases the proportion of CD8+/CD4+ T lymphocytes, delaying tumor development (79). Multiple observations on the beneficial effects of probiotics indicate the use of probiotic bacterial strains, especially from the genera Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus, Enterococcus, and, less so, from the genera Bacillus and Saccharomyces, for colonization of the gut after antibiotic treatment, which unbalances the gut microbiota.

Furthermore, a diet enriched in Lactobacillus acidophilus, such as some cheeses, some kefir, kombucha, is correlated with reduced risk of colorectal cancer incidence in mice. Lactobacillus rhamnosus GG strain has proapoptotic and antiproliferative effect on murine (HGC-27) and human (Caco-2, DLD-1 and HT-29) colon carcinoma cells, reducing IL8 levels, Bacillus polyfermenticus species, Bacillus subtilis, Bifidobacterium lactis, Bifidobacterium adolescentis, Clostridium butyricum, Enterococcus faecium, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus fermentum, Lactobacillus delbrueckii, Lactobacillus helveticus, Lactobacillus paracasei, Lactobacillus pentosus, Lactobacillus plantarum, Lactobacillus salivarius, Lactococcus lactis, Pediococcus pentosaceus, Propionibacterium acidopropionici and Streptococcus thermophilus reduce the potency of Caco-2, HT-29, SW1116, HCT116, SW480, DLD-1 and LoVo colon carcinoma cells (75), Lactobacillus acidophilus SNUL strains, Lactobacillus casei YIT9029 and Bifidobacterium longum HY8001 suppress proliferation of human colorectal carcinoma SNUC2A and gastric carcinoma SNU1 cells and Bacillus polyfermenticus inhibits colony formation of human colon epithelial cells NMC460. These studies and those revealing immunomodulatory effects of probiotics on cytotoxic T lymphocytes and NK cells indicate their suitability for inclusion in adjuvant therapy, alongside chemotherapy and immunotherapy, in the treatment of some cancers (80).

Synbiotics are combinations between probiotic microorganisms and specific prebiotic compounds, which have the advantage of their simultaneous administration and promote the survival, growth (81) and rapid colonization of probiotics in the gut in a short time, restoring balance and inducing eubiosis state. Synbiotic containing the probiotic Lactobacillus gasseri 505 and prebiotic consisting of Maclura tricuspidata Carrière (synonym Cudrania tricuspidata Bureau) leaf extract in fermented milk shows protection against azoxymethane/dextran sodium sulfate-induced colitis and associated colon carcinoma. It suppresses the incidence of colonic tumors and reduces colonic mucosal lesion formation by inhibiting the secretion of the pro-inflammatory cytokines TNF-α, IFN-γ, IL1-β and IL-6, the inflammation-associated enzymes iNOS and COX2 and the anti-apoptotic factors Bcl2 and BclxL, stimulating the expression of the anti-inflammatory cytokines IL4 and IL10 and the pro-apoptotic factors Tp53, p21 and Bax. At the same time, the synbiotic combination inhibited the growth of bacteria of the genus Staphylococcus and maintained the growth of bacteria of the genera Lactobacillus, Bifidobacterium and Akkermansia, which produce short-chain fatty acids and have antitumor effects, suggesting that synbiotic administration may be a promising adjuvant therapy for colorectal carcinoma (82).

Postbiotics are molecules, cell fragments or whole cells derived from microbial cells after they have been killed or inactivated, that produce beneficial health effects. Thus, in viable or inactivated form, Bifidobacterium bifidum MIMBb75 reduces the effects of irritable bowel syndrome, Lactobacillus gasseri CP2305 in viable form has the same effect and in inactivated form regulates bowel function, and Akkermansia muciniphila ATCC BAA-835 in viable or inactivated form improves the metabolism of overweight or obese people (83) and can be used in the prevention of certain types of tumors. On tumor cell lines, postbiotics produce some effects that recommend them as adjuvants in the treatment of some neoplasia. In cervical cancer, acellular Lactobacillus rhamnosus supernatant induces apoptosis of HeLa cells; in colorectal cancer, short chain fatty acid from Clostridium butyricum activates the Wnt/β-catenin signaling pathway in HCT-116, Caco-2 and HCT-8 cells, cell-free pentasaccharide from Lactobacillus acidophilus induces apoptosis of Caco-2 cells, cell-free supernatant from Lactobacillus fermentum induces apoptosis of HT-29, HCT-116, DLD-1 and WiDr cells, heat-killed Lactobacillus kefiri is apoptotic for HT-29 cell line, Lactobacillus paracasei IMPC2.1 and heat-killed Lactobacillus rhamnosus GG induce apoptosis of DLD-1 cells, cell-free supernatant from Lactobacillus pentosus Miny-148 activates cell-mediated cytotoxicity against HT-29 cells, and heat-killed acellular extract of Lactobacillus plantarum A7 activates cell-mediated cytotoxicity against Caco-2 and HT-29 cells; in gastric cancer, heat-killed Lactobacillus paracasei IMPC2.1 induces apoptosis of HGC-27 cells; in breast cancer, cell-free supernatant of Escherichia coli, cell-free pentasaccharide from Lactobacillus acidophilus and heat-killed, cytoplasmic fractions of Enterococcus faecalis and Staphylococcus hominis induce apoptosis of MCF-7 cells, short chain fatty acid from Escherichia coli KUB-36 having anti-inflammatory effect, acellular extracts from heat-killed Lactobacillus acidophilus KP94283 and Lactobacillus plantarum KP894100 produce cell-induced cytotoxicity on the MCF-7 line, acellular extract of Lactobacillus acidipiscis ITA44 and Lactobacillus pentosus ITA23 produce cell-induced cytotoxicity on the MDA-MB-23 line, and heat-killed Saccharomyces cerevisiae induce apoptosis of MCF-7, ZR-75-1 and MDA-MB-23 cells; in lung carcinoma, cell-free supernatant of heat-killed Mycobacterium indicus pranii induces apoptosis and cell cytotoxicity of A549 and CaSki cells, and on the A375 skin cancer cell line, cell-free extract of Lactobacillus plantarum L-14 induces apoptosis. In vivo studies indicate apoptotic or immune-stimulating activity on colorectal, breast and pancreatic cancers (84) ( Figure 2 ).

Cancer chemotherapy, referring to the use of traditional cytotoxic chemotherapeutic agents, has been shown to be impacted by the gut microbiome in murine models, particularly with therapies involving cyclophosphamide (CTX) and oxaliplatin (85). Cyclophosphamide can alter the composition of the gut microbiota, leading to the translocation of certain gram-positive bacteria into secondary lymphoid organs triggering the production of “pathogenic” T helper 17 (pTh17) cells while enhancing the response of memory T helper 1 (Th1) cells, thereby bolstering the host immune system (85).

The negative effects of microbiota on chemotherapy are of three types: metabolization and reduced efficacy, increased toxicity with adverse effects, and development of resistance to treatment. For example, the bacterial enzyme uridine phosphorylase (homologue of human uridine phosphorylase) is involved in modulating the activity of capecitabine metabolites. Uridine phosphorylase has a dual role in cancer and is secreted by tumor cells in marginally invasive regions of tumors, especially in those in which TP53 (negative regulator of uridine phosphorylase) is inactivated, and in macrophages in tumor stroma, by a mechanism that includes TNFA and NF-kB, but also by some bacteria, such as Escherichia coli and Parabacteroides distasonis (86). Gemcitabine, a cytidine analogue used in the first-line treatment of solid tumors of the bladder, pancreas, ovary and breast including pancreatic ductal adenocarcinoma, suppresses cell cycle progression from G1 to S phase and kills cells with active DNA synthesis during S phase (87). In colon carcinoma models, gemcitabine (2’,2’-difluoro-2’-deoxycytidine) is converted to 2’,2’-difluorodeoxycytidine, an inactive metabolite, by an isoform of bacterial cytidine deaminase, produced by Mycoplasma hyorhinis, other intratumoral Gamma-proteobacteria and the oral pathogenic bacteria Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, which by this mechanism reduce its efficacy by 10 to 60-fold and induce tumor cell resistance to this drug (88).

Present in the oral cavity, where it causes periodontal disease, Fusobacterium nucleatum induces overexpression of TLR4 and BIRC3 (Baculoviral IAP Repeat Containing 3), activates the TLR4-MYD88d and ULK1/ATG7 autophagy network signaling pathways, and genomic loss of miR-18a* and miR-4802, favoring the acquisition of resistance to 5-fluorouracil treatment in people with colorectal cancer (89). Treatment with 5-fluorouracil produces gut dysbiosis, characterized by overgrowth of Lachnospiracea_NK4 A136, Bacteroides, Odoribacter, Mucispirillum and Blautia and reduction of Coriobacteria and Deltaproteobacteria taxa (90), with induction of side effects, and oral dysbiosis, favoring depletion in Streptococcus, Actinomyces and Veillonella and multiplication of Prevotella oris and Fusobacterium nucleatum, which favor the occurrence of oral mucositis, as a side effect of chemotherapy (91).

Gut microbiota and fecal microbiota transplantation may play an important role in the limitation of oxaliplatin adverse effects, including peripheral neurotoxicity (numbness of extremities, hyperalgesia), which are not present in laboratory animals pretreated with a mixture of antibiotics (92).

Doxorubicin is a drug of the anthracycline class, naturally produced by the actinobacterium Streptomyces peucetius var. casieus and used in the treatment of several types of tumors, which it inhibits by inducing damage to genetic material. However, taken in high doses, it has side effects on the heart. Under anaerobic conditions, the electron transport chain NADH dehydrogenase enzyme produced by Streptomyces WAC04685 inactivates it by deglycosylation (93), and a molybdopterin-dependent enzyme from Escherichia coli BW25113 and Klebsiella pneumoniae degrades it, reducing its efficiency. Raoultella planticola has an antagonistic effect on them, restoring the therapeutic efficacy of doxorubicin (94).

Irinotecan/CPT-11 is a drug used together with 5-fluorouracil in the treatment of colon cancer. Administered in glucuronic acid conjugated form, irinotecan is deconjugated by the enzyme β-glucuronidase secreted by Escherichia coli, favoring the manifestation of drug toxicity, reduced antitumor efficacy and the onset of severe diarrhea, one of its main side effects (95). Administration of a low dose of amoxapine, an antidepressant drug that inhibits β-glucuronidase without affecting the gut microbiota, together with irinotecan prevents diarrhea and contributes to the manifestation of the antitumor activity of the latter (96).

Preclinical studies have demonstrated that depletion of the gut microbiota can sustain the survival of transferred T cells in a cervical cancer model treated with adoptive T cell therapy (ACT), reliant on systemic CD8α + dendritic cells (DCs) and interleukin-12 (IL12) (97).

Specific members of the gut microbiome, namely Enterococcus hirae and B. intestinihominis, can impact the clinical efficacy of CTX in cancer treatment by reducing regulatory T cells and enhancing the immune response of MHC class I-restricted cytotoxic T cells (CTLs) against the tumor, thereby modifying the tumor microenvironment (56).

Another study conducted on the FOLFOX chemotherapy regimen (comprising 5-FU, leucovorin calcium, and oxaliplatin) in a colorectal cancer model revealed that certain microbiome compositions can trigger the activation of nuclear transcription factor-κB (NF-κB) and enhance the production of interleukin-6 (IL-6) and tumor necrosis factor (TNF). This cascade promotes inflammation and leads to mucosal damage (98). However, the probiotic Lactobacillus rhamnosus has been shown to mitigate chemotherapy-induced mucositis by modulating the proinflammatory response and suppressing intrinsic apoptosis in intestinal injury.

The intestinal microbiota can influence the adverse drug reactions associated with irinotecan-based chemotherapy by reactivating the metabolite of SN-38 glucuronide (99). In the study by Guthrie et al., the abundance of Faecalibacterium prausnitzii and specific Bacteroides species varied significantly among cohorts stratified based on glucuronide metabolism. Inhibiting microbial β-glucuronidases could potentially alleviate severe side effects induced by irinotecan, such as severe diarrhea (99).

The advent of immune checkpoint inhibitors (ICIs) in cancer treatment, encompassing monoclonal antibodies directed against programmed death receptor (PD-1), programmed death receptor ligand (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) receptor, has heralded a transformative era in cancer therapy, drastically altering the prognosis of numerous malignancies. These agents are extensively employed in the management of advanced-stage cancer but the emergence of primary and secondary resistance to cancer treatment poses a significant challenge and can profoundly impact patient outcomes (100). Recently, emerging evidence has underscored the profound influence of the gut microbiota on tumor response to ICIs, as demonstrated in both clinical cohorts and preclinical mouse models.

Several studies have identified Bacteroidetes as a biomarker indicating non-responsiveness to immune checkpoint inhibitors in patients with metastatic melanoma (MM) (101, 102).(Its presence may reduce response rates and dampen systemic and antitumor immunity, potentially lowering the risk of local inflammation such as ICI-induced colitis. However, specific strains of Bacteroidetes, such as Bacteroides thetaiotamicron and B. caccae, have been linked to an effective therapeutic response (103).

Radiation therapy can also trigger apoptosis of intestinal cells and disrupt the composition of the gut microbiome, resulting in intestinal inflammation, which can manifest as symptoms like diarrhea and fatigue (104). Side effects such as fatigue, nausea, vomiting, and diarrhea associated with radiation therapy may be alleviated by probiotics like Lachnospiraceae and Enterococcaceae, indicating a potential for reducing radiation-induced damage through modulation of the gut microbiome (105). Notably, findings from a randomized clinical trial revealed that combining probiotics with radiation therapy in patients with nasopharyngeal carcinoma undergoing concurrent radiochemotherapy could significantly enhance host immunity and alleviate oral mucositis (OM) associated with radiochemotherapy by altering the gut microbiota (106).

Current research is focused on locally resident microbiota and intratumor microbiota. Locally resident microbiota, particularly those inhabiting the gastrointestinal tract and other parts of the digestive system, have been identified as closely linked to the carcinogenesis of their respective organs. Previous studies have demonstrated associations between susceptibility to various cancers, such as oral squamous cell carcinoma (OSCC), esophageal cancer, gastric cancer, gastric diffuse large B cell lymphoma (DLBCL), colorectal cancer (CRC), gastric mucosa-associated lymphoid tissue lymphoma (MALT), hepatocellular carcinoma (HCC), pancreatic cancer, gallbladder cancer, lung cancer, breast cancer, and prostate cancer, and locally resident microbiota (107).

However, the relationship between locally resident microbiota and the efficacy of therapy remains under investigation. Notably, for patients with colorectal cancer (CRC), the gut microbiome also constitutes the locally resident microbiota at the tumor site. The significance of the intratumor microbiome in gastrointestinal cancer also plays a pivotal role in determining the effectiveness of cancer treatment. In a study focusing on murine colon cancer, Geller discovered that intratumor Gammaproteobacteria can impact gemcitabine metabolism, leading to resistance against the drug (88).

Eliminating bacteria residing within pancreatic cancer was associated with the immune response to PDAC. Modifying the tumor microenvironment to hinder the infiltration of myeloid-derived suppressor cells (MDSCs) promoted the differentiation of M1 macrophages which, in turn, facilitated the differentiation of Th1 cells and augmented the population of activated CD4+ and CD8+ T cells (108). The elimination of bacteria could potentially alter the response of PDAC patients to ICIs by increasing the expression of PD-1. Regarding the precise mechanism of immune reprogramming, the microbiome associated with PDAC can activate specific Toll-like receptors in monocytic cells, leading to the induction of a tolerogenic immune program that suppresses both innate and adaptive immunity (108).

A recent study compared bronchial brushing samples from 24 lung cancer patients and 18 healthy controls to investigate the airway microbiome. Samples from patients included unilateral lobar tumor sites and paired samples from both the cancerous and noncancerous sites. The findings revealed differences in the microbiota profiles between cancerous sites of lung cancer patients and healthy controls, with lower microbial diversity observed in cancerous sites and healthy controls compared to noncancerous sites. The tumor tissue exhibited higher abundance of Streptococcus and Neisseria, whereas Staphylococcus and Dialister were more prevalent in normal tissue. Additionally, there was a gradual shift in microbiota abundance from normal tissue to noncancerous site tissue to cancerous tissue in lung cancer patients. These findings suggest that the lung microbiota can significantly influence the tumor microenvironment, impacting cancer progression and patient prognosis beyond just the cancerous site (109).

The microbiota within tumors could serve as a source of non-self antigens, capable of being recognized by T cells and influencing responses to therapy. For instance, a recent analysis of metastases from 17 melanoma patients revealed a variety of peptides binding to MHC class I and MHC class II, originating from 41 bacterial species (110). Moreover, T cells specific to the microbiota might contribute to certain immune checkpoint blockade (ICB)-induced immune-related adverse events. An investigation demonstrated that ICB-induced dermatitis might arise from T cells targeting epithelial cells presenting antigens from skin commensals. In mice, the introduction of Staphylococcus epidermidis to the skin during anti-CTLA4 treatment prompted epithelial inflammation driven by S. epidermidis-specific T cells producing IL-17 (110).

Intratumoral microbes have the ability to evade immune responses, impacting tumor development by fostering an immunosuppressive environment and deactivating immune cells. For example, F. nucleatum influences the tumor immune landscape by specifically attracting tumor-infiltrating myeloid cells such as CD11b+ myeloid cells, MDSCs, tumor-associated macrophages, classical myeloid DCs, and CD103+ regulatory DCs, thereby enhancing tumorigenesis (111). Moreover, F. nucleatum has the ability to attach to and trigger the T Cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT), as well as the carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) receptors present on human NK cells and other lymphocytes thereby suppressing the function of anti-tumor immune cells in colorectal cancer (CRC) (112).

In a study conducted on mice, it was found that Pasteurella showed a positive correlation with cytotoxic CD8+ tumor-infiltrating lymphocytes (TILs) and a negative correlation with M2-like macrophages. Conversely, Coriobacteriaceae exhibited a positive association with M2-like macrophages and a negative association with CD8+ cells. These various immune reactions play a significant role in the onset and progression of lung tumors (113).

While the intratumor microbiome can diminish the potency of chemotherapeutic agents, suppress the expression of major histocompatibility complex (MHC) class I, and elevate MDSC numbers, it can also prompt alternative immune checkpoints and impede lymphocyte clonal expansion (114). Conversely, it has the capacity to directly engage the innate immune system, generate anti-inflammatory cytokines, and heighten the expression of targetable checkpoint molecules, potentially bolstering cancer immunity (114). This dual impact on the immune microenvironment highlights the complexity of the tumor microbiome and warrants further investigation across diverse cancer types.

In essence, the influence of locally resident microbiota or intratumor microbiota on cancer therapy remains inadequately explored (115). Although the roles of certain locally resident or intratumor bacteria have been confirmed in select cases, the majority of studies have focused on gut-related scenarios. Evidence regarding the interaction between cancer therapy efficacy and locally resident microbiota in other areas of the digestive tract is lacking. Nevertheless, there are indications linking locally resident microbiota with local inflammation and cancer progression, suggesting that modifying the microbiome could enhance patient prognosis.

Microorganisms are an important component of the human organism, forming a dense ‘organ’ with a specific signature of each individual and with a role in nutrition, in regulating epithelial development and in training innate immunity. The body includes numerous non-sterile sites, each developing a characteristic microbiota. Under conditions of eubiosis, it develops relationships of commensalism and symbiosis with the organism, contributing to an important extent to health and protecting it from some diseases, but under conditions of dysbiosis, microorganisms are involved in several pathologies, including cancer. Many recent papers highlight the roles of human microbiota in different aspects of carcinogenesis, from cancer susceptibility and progression to anticancer therapy response, but the elucidation of the mechanistic implications is still in its infancy. Microbiota can modulate anticancer therapy efficacy and toxicity, and also influence resistance to anti-cancer drugs due to its ability to metabolize drugs and xenobiotics and to modulate host inflammation and immune responses. Microbiome-based therapeutic interventions may be able to correct dysbiosis, maximize the response to anticancer treatments and prevent carriage of antimicrobial-resistant pathogens. A better knowledge of gut microbiota roles in cancer will enable us to develop novel microbiome derived biomarkers, anticancer treatment strategies and subsequently improve the cancer patients’ outcome.

MC: Writing – original draft. MCC: Writing – original draft, Conceptualization, Formal analysis, Funding acquisition. GM: Writing – original draft. NC: Writing – review & editing. LB: Writing – review & editing. CB: Writing – review & editing. ST: Writing – review & editing, Formal analysis. MM: Writing – review & editing. RF: Writing – original draft. SG-M: Writing – review & editing. GP: Writing – original draft, Writing – review & editing.