Introduction  

The gut microbiota, consisting of a complex community of billions of microorganisms, mainly residing in the gastrointestinal tract, is essential for maintaining homeostasis in humans [1]. This vast microbial ecosystem participates in key physiological functions such as nutrient digestion, vitamin synthesis, and the development and modulation of the immune system [2]. However, this microbiota is not only beneficial; it can also play a harmful role, notably by influencing carcinogenesis, i.e. the process of cancer formation and development. Some bacterial strains present in the gut microbiota can, in fact, promote the onset and progression of tumors, while others can play a protective role by preventing or limiting tumor development. This duality, where the microbiota acts as both an oncogenic and anticancer agent, is attracting increasing interest in oncological research [3].

At first glance, the relationship between the gut microbiota and cancer may seem unexpected. However, recent research has highlighted the basic role that these microorganisms play in modulating the immune system, thus influencing the development, progression, or regression of tumors [4]. On the one hand, some bacteria in the microbiota can promote carcinogenesis through different mechanisms [5]. They can induce chronic inflammatory responses in the intestine, produce carcinogenic compounds, modify the expression of host genes, and disrupt immune responses, thus promoting the transformation of normal cells into cancer cells [6].

The oncogenic role of the intestinal microbiota is largely based on its ability to induce chronic inflammation, a pathological state that can damage the DNA of intestinal cells and promote their mutation. These genetic mutations, often considered precursors to tumor development, occur when a persistent inflammatory environment activates pro-inflammatory signaling pathways. This inflammatory context increases the risk of cancer because it creates a breeding ground for the proliferation of abnormal cells. Furthermore, some toxins produced by gut bacteria can directly alter DNA, causing double-strand breaks that facilitate the onset of oncogenic mutations. This toxin production, combined with chronic inflammation, creates a microenvironment conducive to tumor cell growth and progression [7].

In addition, the gut microbiota can influence carcinogenesis by modulating host cell gene expression through epigenetic mechanisms. For example, it can regulate DNA methylation, a key epigenetic process that controls gene expression. Abnormal regulation of DNA methylation can lead to the suppression of cancer-protective genes, such as tumor suppressor genes, thereby increasing the risk of tumor development. In addition, epigenetic modulation can also lead to the increased expression of pro-inflammatory cytokines, which not only stimulate cell proliferation but also promote tumor vascularization, facilitating their development and dissemination [8].

On the other hand, despite these potential oncogenic effects, the gut microbiota also has notable anticancer properties. Some bacteria play a protective role by enhancing host immune responses, which is essential for the detection and elimination of tumor cells. By activating key signaling pathways within the innate immune response, the microbiota can increase the efficacy of immune therapies, allowing the immune system to better target and eliminate cancer cells. This improvement in immune defenses can limit tumor progression and reduce the risk of relapse after treatment [4].

In addition, the gut microbiota can stimulate effector and memory T-cell responses, which are essential for the continued destruction of cancer cells and for the prevention of recurrence [9]. These T-cell immune responses are enhanced by the ability of the microbiota to reduce populations of immunosuppressive cells, such as regulatory T cells (Tregs) and marrow-derived suppressor cells (MDSCs). By reducing the influence of these cells that usually inhibit antitumor immune responses, the microbiota promotes a more effective and sustained immune response against tumors [10].

Furthermore, the microbiota also protects against cancer by producing metabolites with anticancer properties. These metabolites, such as short-chain fatty acids like butyrate, are able to induce apoptosis, or programmed cell death, of cancer cells, which prevents their proliferation [11]. The ability of these metabolites to induce apoptosis has been demonstrated in various animal models, where their presence not only reduced the incidence of cancer but also prolonged the survival of subjects with tumors. These observations suggest that the production of metabolites by the microbiota could be exploited for the development of new anticancer therapeutic strategies [12].

This study aims to analyze the ambivalent roles of the gut microbiota in carcinogenesis, highlighting its ability to both promote and inhibit tumor development. By examining the complex interactions between gut bacteria and the tumorigenesis process, this review explores how certain bacterial strains can modulate the formation and progression of neoplasms, notably by inducing chronic inflammation and producing genotoxic molecules. At the same time, it focuses on the anticancer properties of other bacteria, capable of regulating the tumor microenvironment favorably, optimizing host immune responses, and inspiring innovative therapeutic strategies.

Gut microbiota       

Overview

The gut microbiota is one of the most studied areas in biology and medicine, largely thanks to international initiatives such as MetaHIT and the Human Microbiome Project, which aim to better characterize and understand this microcosm. This microbiota, weighing between one and five kilograms in adult humans, is composed of approximately 10¹⁴ microorganisms, which is ten times greater than the number of human cells in our body. Although bacteria make up the majority, the microbiota also includes archaea, viruses, and eukarya, making it an incredibly diverse ecosystem [13].

Among bacteria, anaerobes dominate, mainly belonging to three major phylogenetic groups: Firmicutes, Bacteroidetes, and Actinobacteria [14-16]. However, the exact composition of the gut microbiota varies significantly between individuals and also changes throughout life. Enterotypes are used to describe these different dominant microbial configurations. The first microbial colonization occurs at birth, and the mode of delivery plays a crucial role in this initial process. During a vaginal birth, the newborn is first colonized by microorganisms from the maternal genital tract, leading to a stabilization of the microbiota around the age of three years. In contrast, a cesarean birth leads to initial colonization by skin germs, which can delay the establishment of the microbiota and has been associated with a higher incidence of chronic inflammatory pathologies, including allergies [17].

Diet is another key factor that modifies the composition of the microbiota. A diet rich in meat and saturated fatty acids favors the growth of Bacteroidetes and the genus Ruminococcus, while a diet rich in fiber and simple sugars favors the genus Prevotella [18]. These variations show how sensitive the microbiota is to environmental influences and how it can be modulated by dietary choices.

Recent research has also revealed that the gut microbiota could be considered a true microbial "identity card". Approximately 57 species of bacteria are common to 90% of the population, defining what is called the "core genome" of the human microbiota (Table 1) [19, 20]. However, despite these commonalities, each individual has a unique microbiota. This uniqueness is influenced by many factors, including geography, with marked differences observed between the microbiotas of people living in remote areas. The greater the geographical distance, the more pronounced the differences between enterotypes will be, although important similarities may still exist [21].

The evolution of the microbiota throughout life is also influenced by age and nutritional status. The Firmicutes group, a minority in children, becomes the majority in healthy adults, representing approximately 45% of the microbiota. Conversely, Proteobacteria, which are decreased in healthy subjects, persist at high levels in malnourished or obese individuals, indicating a potential link between microbiota composition and various pathophysiological states. These observations highlight the importance of the gut microbiota in human health and the need to better understand the factors that influence its composition throughout life [22].

Physiological roles

The gut microbiota performs several physiological functions that are essential for human health. One of its most important contributions concerns the regulation of angiogenesis, muscle development, and energy production. Gut bacteria release hundreds of enzymes that facilitate the digestion of plant-derived sugars, such as pectins and arabinose, allowing the body to maximize energy extraction from these compounds. In turn, the fermentation of these sugars by the bacteria feeds themselves, creating a cycle of mutualism that benefits the host [23].

In addition to digestion, the bacteria of the microbiota are also able to synthesize vitamins, amino acids, and short-chain fatty acids (SCFAs), which play an important role in the host metabolism. These SCFAs, such as butyrate and propionate, do not only provide energy; They are also involved in the regulation of inflammation and modulation of the immune response, thus providing protection against various inflammatory pathologies and potentially against the development of cancer [24].

The gut microbiota is also essential for the development of the enteric nervous system, which is one of the oldest nervous systems that has emerged during evolution. This system, often called the "second brain", works closely with the central nervous system to regulate intestinal motility and other gastrointestinal functions. In addition, gut bacteria participate in the regulation of certain genetic processes, influencing key aspects such as immune responses, bacterial proliferation, and inflammation. For example, disturbances in the composition of the microbiota have been associated with genetic alterations in animal models of inflammatory bowel disease (IBD), highlighting the link between the microbiota and gene regulation [25].

The role of the microbiota as a barrier against pathogens and its importance in maintaining the immune system is also important. Studies on germ-free mice, devoid of microbiota, have shown significant deficiencies in their immune systems. These mice have smaller Payer's plaques (lymphoid structures in the intestine), a decrease in the number of plasma cells, IgA, and intraepithelial lymphocytes. These immune deficiencies can be corrected by recolonization of microbiota from healthy mice, illustrating the importance of the microbiota in the maturation and optimal functioning of the immune system [26].

However, although the microbiota is necessary for adequate maturation of the immune system, it is not sufficient on its own to guarantee complete protection against pathogens. Firmicutes, a dominant bacterial group, are distributed differently depending on the health status and are associated with variable protection against infections. The first microbial colonization, which occurs at birth, is particularly basic to stimulate an optimal immune response, especially if this colonization is by commensal bacteria capable of synthesizing SCFAs such as butyrate and propionate. These SCFAs promote the differentiation of regulatory T cells (LTreg) via acetylation of the FoxP3 locus, thereby reducing inflammation by inhibiting the NFKb pathway. In addition, they play a role in controlling the Th17 cell pool, which could provide protection against cancerization by modulating inflammatory responses. These observations highlight the importance of the gut microbiota not only in maintaining daily health but also in preventing chronic diseases and cancer [27].

Intestinal bacteria and their involvement in carcinogenesis

Dysbiosis and disruptions of the gut microbiota

The gut microbiota, a complex and dynamic ecosystem, can undergo significant disruptions, often referred to as dysbiosis, in response to various environmental factors. Among these factors, diet plays a key role, as does exposure to irritants to the intestinal mucosa such as alcohol, tobacco, airborne microparticles, pesticides, and heavy metals. Overuse or inappropriate use of antibiotics is also a major cause of dysbiosis, leading to imbalances that can have adverse health consequences [28].

Dysbiosis has been closely associated with several chronic diseases, including allergies, diabetes, obesity, autism, and inflammatory bowel diseases (IBD) such as Crohn's disease and irritable bowel syndrome. These pathologies are often characterized by chronic inflammation, a biological process that is recognized as a crucial preliminary step in the development of cancer, particularly in the context of carcinogenesis [29].

Chronic intestinal inflammation, in particular, represents a set of conditions that can progress to malignant tumors after several years. Although the causes of these inflammations are often multifactorial and poorly understood, the close relationship between immunity, microbiota, and cancer development is evident. Studies have shown that patients with these pathologies often have significant differences in the composition and diversity of their intestinal microbiota. This observation has led to the hypothesis that restoring the microbial balance could prevent the progression of these diseases to cancerous states. Treatments such as fecal microbiota transplantation, where bacteria from a healthy donor are transplanted into a patient, have shown promising results, particularly in the treatment of Crohn's disease [30].

Pro-oncogenic mechanisms of intestinal bacteria

The intestinal microbiota, although generally beneficial, can play a pro-oncogenic role when imbalanced. Pro-oncogenic bacteria contribute to cancer development through various pathogenic mechanisms. One of the key mechanisms is the stimulation of cell proliferation. Some bacteria in the microbiota can activate signaling pathways that increase host cell viability, thereby promoting uncontrolled tumor cell growth [31].

In addition, these bacteria can exacerbate the production of reactive oxygen species (ROS), causing DNA damage and genomic instability, conditions favorable to carcinogenesis. They can also modulate the expression of tumor suppressor genes, decreasing them while increasing the expression of oncogenic genes, which creates an environment conducive to tumor progression [32].

Furthermore, some bacteria can recruit immune suppressor cells into tumors, thereby thwarting antitumor immune responses and allowing tumors to grow. Activation of inflammasomes by these bacteria creates an inflammatory microenvironment that promotes cancer progression. Lastly, these bacteria can lessen the efficacy of anticancer therapies like chemotherapy and immunotherapy by interfering with immune responses and causing alterations in cells [33].

Bacterial strains associated with carcinogenesis

The gut microbiota, a complex community of microorganisms inhabiting the gastrointestinal tract, is essential for the preservation of human health. However, imbalances within this microbial community, referred to as dysbiosis, can cause various disorders, including the development of cancers [34]. Among the many microorganisms present in the intestine, certain bacterial strains have been recognized for their pro-oncogenic role, and also they participate in the initiation and progression of tumors (Table 2).

Fusobacterium nucleatum is one of the most studied bacteria for its involvement in colorectal cancer. It stands out for its ability to disrupt adaptive immunity by inhibiting antitumor T-cell responses, allowing cancer cells to proliferate undetected by the immune system. F. nucleatum also activates inflammatory signaling pathways, such as NLRP3, and interacts with the TIGIT receptor, inhibiting the cytotoxic function of NK cells. In addition, it influences tumor cell glycolysis via the ANGPTL4 protein, enhancing tumor aggressiveness [35].

Bacteroides fragilis is another intestinal bacterium strongly associated with colorectal cancer. It promotes cancer cell proliferation by activating the RHEB/mTOR pathway, which is essential for tumor cell growth and survival. B. fragilis also produces the toxin BFT, which causes DNA damage and induces chronic inflammation, two processes closely linked to carcinogenesis. This bacterium is also involved in intestinal mucosal hyperplasia, a precursor state of cancer, and the production of ROS, exacerbating oxidative damage and increasing the risk of cancer [36].

Escherichia coli, although generally harmless in the intestine, becomes pathogenic when it produces colibactins, molecules capable of causing DNA breaks, a key event in the malignant transformation of cells. E. coli also promotes epithelial-mesenchymal transition (EMT), a process by which epithelial cells acquire migratory and invasive properties, facilitating metastasis [37].

Clostridium difficile, mainly known for its severe intestinal infections, is also involved in carcinogenesis. This bacterium produces the toxin TcdB, which disrupts cellular signaling pathways, leading to cytoskeletal alterations, apoptosis, and chronic inflammation. These processes create an environment conducive to tumor growth and colorectal cancer development [38].

Peptostreptococcus anaerobius is a bacterium recently identified as being associated with colorectal cancer. It interacts with integrin α2/β1, overexpressed on colon cancer cells, stimulating their proliferation and migration. This interaction promotes tumor progression, supported by a local inflammatory environment conducive to cancer cell growth [39].

Hungatella hathewayi contributes to carcinogenesis through its ability to regulate DNA methylation, an important epigenetic process in the regulation of gene expression. By promoting the methylation of tumor suppressor genes, this bacterium facilitates the growth and proliferation of cancer cells, particularly in colorectal cancer [40].

Eubacterium, a commensal bacterial genus, is involved in chronic inflammation through activation of the transcription factor NF-κB. This activation supported by Eubacterium endotoxins creates a microenvironment favorable to tumor cell proliferation and colorectal cancer progression [41].

Streptococcus gallolyticus is closely linked to colorectal cancer by its ability to induce the expression of pro-inflammatory cytokines such as IL-1 and COX-2, as well as the chemokine IL-8, which promotes tumor growth and tumor vascularization. This bacterium also impairs the immune response, allowing uncontrolled proliferation of cancer cells [42].

Campylobacter jejuni, mainly associated with gastrointestinal infections, is also implicated in colorectal cancer. This bacterium produces a cytolytic distensive toxin (CDT) that causes DNA damage, inducing genomic instability, a key precursor to carcinogenesis. Furthermore, C. jejuni exacerbates chronic inflammation, creating an environment favorable to tumor development [43].

Anti-oncogenic role of microbiota in tumor regression

The tumor microenvironment (TME) plays a central role in tumor development and progression. This microenvironment consists of tumor cells surrounded by blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, various signaling molecules, and the extracellular matrix. The rapid proliferation of tumor cells leads to the formation of immature vascular structures, thus creating a hypoxic microenvironment. This condition, coupled with high interstitial pressure and fibroblast density, limits the efficacy of antitumor drugs. However, some specific anaerobic bacteria can invade and colonize this hypoxic microenvironment, playing an anti-oncogenic role by promoting tumor regression [44].

Invasion of anaerobic bacteria in hypoxic TME

Anaerobic bacteria possess a unique ability to colonize hypoxic areas of tumors. These regions are often resistant to conventional therapies due to poor drug penetration. However, some bacterial strains not only manage to survive in these harsh conditions but also exert antitumor effects by directly killing cancer cells or by inducing innate and adaptive immune responses against infected tumor cells [45].

Salmonella typhimurium has shown an ability to specifically target tumors and colonize hypoxic microenvironments, contributing to tumor regression. Similarly, bacteria such as Listeria monocytogenes and Clostridium novyi-NT (a strain of Clostridium modified to eliminate the α-toxin gene) have been studied for their ability to directly attack tumor cells and induce immune responses favorable to tumor regression [46].

Stimulation of innate and adaptive immune responses

Some bacteria have the ability to induce innate and adaptive immune responses that play a basic role in tumor regression.

Salmonella typhimurium is able to stimulate a potent immune response against tumor cells by triggering the production of pro-inflammatory cytokines such as interleukin-1β. This cytokine promotes the activation of M1 macrophages, which are associated with antitumor responses while reducing the population of M2 macrophages, which generally support tumor progression [47].

Similarly, Listeria monocytogenes is known to induce long-lasting effector and memory T-cell responses, essential for the continued destruction of cancer cells and the prevention of relapse. These bacteria can also reduce the populations of regulatory T cells (Treg) and marrow-derived suppressor cells (MDSC), which normally inhibit antitumor immune responses [48].

Regulation of systemic anti-tumor immunity

Bacteria that possess low cytotoxicity toward tumor cells, such as Bifidobacterium infantis, play a key role in regulating systemic anti-tumor immunity. These bacteria can modulate the tumor environment by increasing the efficacy of immune therapies. For example, B. infantis has been shown to facilitate immunotherapies based on CD47 blockade by activating the STING signaling pathway, which is essential for the innate immune response. Studies have also shown that Bifidobacterium bifidum can increase the biosynthesis of immune-stimulating molecules and metabolites, leading to better recognition and destruction of tumor cells by the immune system [49].

Bacterial therapies

Some bacteria have the ability to thrive in oxygen-deficient environments, such as solid tumors, which are often characterized by hypoxic or anoxic conditions. This metabolic adaptation allows these bacteria to circumvent the complexities of tumor and immune biology. Unlike passive systemic treatments, these bacteria, considered “biologically active agents,” are particularly effective at targeting and colonizing tumor tissues. Their specific metabolism, their ability to move in a directed manner, and their sensitivity to the tumor environment give them increased selectivity for cancer tissues, potentially offering safer and more targeted treatments [50].

The development of new therapeutic approaches in oncology is based on the need to accurately select and detect tumors. The distinct physiological properties of some bacteria, which can be genetically modified, if necessary, perfectly meet these requirements and they can localize and multiply in tumor tissues when administered intravenously in animal models. These bacteria can then exert direct toxicity on tumor cells by synthesizing and releasing cytotoxic molecules on-site while creating nutritional competition within the tumor [51].

Research using mice as test subjects has produced encouraging outcomes, including tumor remissions and minimal damage in certain cases. However, despite demonstrating good tolerance, clinical trials have shown inconsistent efficacy, and increasing doses to improve efficacy has resulted in significant toxicity. Despite these challenges, therapies based on the use of bacteria continue to be explored with encouraging results in preclinical and clinical studies [52].

Clostridium novyi-NT

Clostridium novyi-NT has emerged as a promising candidate for cancer therapy, particularly after preliminary findings revealed its potential to target and destroy tumor cells. This strain is a modified version of Clostridium novyi, a strictly anaerobic bacterium known for its ability to thrive in oxygen-deficient environments, such as hypoxic solid tumors. Its ability to selectively colonize these environments and induce tumor cell lysis makes it a subject of interest for anticancer therapies (Figure 1) [53].

Initially, studies focused on Clostridium histolyticum M-55, an avirulent strain tested in animal models for colon tumors and melanoma, but clinical results were disappointing. Subsequently, a selection process identified Clostridium novyi as the most effective strain for colonizing tumors and inducing carcinolytic effects, despite its sensitivity to oxygen toxicity. This strain initially produced a lethal α-toxin, which led to the development of the Clostridium novyi-NT (Non-Toxigenic) strain via heat treatment to destroy the toxin-producing system [54].

Clostridium novyi-NT has a unique advantage as targeted therapy, as its strict requirement for an anaerobic environment makes it specific to hypoxic tumors, minimizing the risk of toxicity in normoxic tissues. Preclinical studies have shown that injection of spores of this strain into tumor-bearing mouse models resulted in a significant reduction in tumor mass. The bacteria act by producing enzymes such as proteases and lipases that degrade tumor tissues while triggering an inflammatory and immune response that enhances the anticancer effect [55].

One of the main mechanisms of action of Clostridium novyi-NT is the induction of local inflammation and stimulation of the immune system, in particular by the production of cytokines such as IL-6, which promote the differentiation of TH17 cells and the activation of CD8+ T lymphocytes, thus enhancing the antitumor immune response. These properties make Clostridium novyi-NT a potential tool for combination therapies, including the use of antiangiogenic agents, radiotherapies, and DNA poisons to maximize efficacy while minimizing toxicity [56].

Clinical trials in animal models have shown that the use of Clostridium novyi-NT alone, or in combination with other treatments, can induce significant tumor regression, even in large tumors. Furthermore, these studies revealed that the immune response induced by Clostridium novyi-NT could provide long-term protection against relapse, with results showing sustained efficacy up to 11 months after initial treatment [57].

However, the therapy is not without risks. Toxicity studies indicated that high doses could lead to reversible side effects, such as hepatomegaly and splenomegaly. The studies also revealed that Clostridium novyi-NT only germinates in hypoxic tumor environments, thus limiting the risks of systemic infection. The addition of antibiotics reduced some side effects, although this also decreased antitumor efficacy. Simple hydration has been suggested as an effective method to mitigate toxicity without compromising therapeutic efficacy [58].

Salmonella typhimurium

Salmonella Typhimurium is an enterobacteria, a Gram-negative bacillus often found in the intestinal lumen of mammals. This microorganism has several characteristics that make it an interesting candidate for therapeutic strategies, particularly in oncology. Its ability to replicate massively in tumor tissues, at a rate 1000 times higher than that observed in healthy tissues, as well as its ability to produce lipopolysaccharide (LPS), are among the factors that give it a unique therapeutic potential (Figure 2) [59].

S. Typhimurium is a motile, facultative intracellular bacterium capable of surviving and replicating within phagocytic cells. The LPS it produces plays an essential role in its virulence, allowing it to protect itself from its environment while stimulating an intense immune response. When invading the intestinal mucosa, this bacterium generates cellular lesions and triggers an inflammatory response marked by an influx of leukocytes, which can lead to symptoms such as diarrhea. These biological properties are exploited in the context of its therapeutic use, where phase I clinical trials have been conducted to evaluate its potential as an anti-tumor agent [60].

The ability of S. Typhimurium to survive in anaerobic conditions allows its intra-tumoral development, thus exploiting the hypoxic environments of tumors. However, this approach is associated with a risk of toxic shock due to the production of LPS. To overcome this problem, a modified strain of S. Typhimurium, called VPN20009, was developed. This strain is auxotrophic for purines, meaning that its metabolism is dependent on these molecules abundant in tumor environments due to cell lysis. In addition, the VPN20009 strain is deleted from the msbB and purI genes, thus reducing virulence and the risk of toxic shock while retaining its ability to colonize tumors [61].

Clinical trials conducted in 1999 showed acceptable tolerance of the VPN20009 strain, but limited efficacy in terms of tumor regression. This low efficacy has been attributed to insufficient tumor colonization and rapid elimination of the bacteria by the body. In response to these limitations, new strains carrying tumor immunological targets, such as Tumors Associated Antigens (TAA), are being developed to improve the recognition and elimination of tumor cells by the immune system [62].

Another promising strain, named A1-R, was designed to be auxotrophic for leucine and arginine, limiting its proliferation to tumor tissues where these amino acids are abundantly available. This strain has shown notable efficacy in the colonization and destruction of lung tumors in mice, as well as anti-angiogenic activity, particularly beneficial in highly vascularized tumors [63].

The two strains described, VPN20009 and A1-R, are the most advanced in the development of Salmonella Typhimurium-based therapies. VPN20009 is currently the only strain to have reached the clinical phase, although obstacles remain. The results obtained so far suggest that S. Typhimurium could become a promising therapeutic agent or treatment vector in the fight against cancers. The future of this research focuses on improving tumor colonization, optimizing safety, and increasing the clinical efficacy of these modified strains [64].

Listeria monocytogenes

Listeria monocytogenes is a Gram-positive, non-spore-forming bacillus that is motile at 20°C, belonging to the Firmicutes group. Its facultative aero-anaerobic metabolism, combined with the presence of catalase and the production of β-hemolysis by listeriolysin O (LLO), allows this bacterium to survive in various environments, including at 4°C, which gives it a psychrophilic character. Listeria is widespread, found in soils, waters, and plants, and approximately 1 to 10% of the human population are thought to be healthy carriers at the intestinal level. Listeria monocytogenes is a pathogenic intracellular bacterium with a tropism for the central nervous system (CNS) and can cause serious infections, particularly in immunocompromised individuals, pregnant women, and newborns. Although listeriosis is relatively rare, with about 200 cases per year in France, it has a high mortality rate of 25 to 30%, even with effective antibiotic therapy. Human contamination occurs mainly through food, particularly via refrigerated products such as raw milk cheeses, cold meats, and seafood  (Figure 3) [65].

In an innovative therapeutic strategy, Listeria monocytogenes has been exploited for its intracellular parasitism properties. The bacterium, thanks to its internalin surface protein, crosses the intestinal barrier and induces its phagocytosis by intestinal antigen-presenting cells (APCs). LLO, when paired with a phospholipase, permits a tiny percentage of bacteria to break free from the phagosome and proliferate in the cytoplasm. Because of its capacity to polymerize actin, Listeria can potentially spread to nearby cells, thus renewing the infectious cycle and effectively reaching tumor cells [66].

To minimize the risk of infection, an attenuated Listeria strain, deleted of the actA and plcB genes, was developed. These genes are respectively responsible for the intercellular mobility of the bacteria and the lysis of cell membranes. Although this strain is avirulent, it retains its ability to stimulate the immune system, making it a promising candidate for anti-tumor vaccination applications [67].

This approach has been successfully tested in mouse models, where Listeria-based vectors have been developed to carry specific tumor-associated antigens (TAAs) such as HPV16 (cervical cancer), Her2/neu (breast cancer), PSA (prostate cancer), and VEGFR-2 (tumor developmental antigen). Preclinical studies have shown that injection of these vectors can induce a strong immune response, sufficient to eradicate the corresponding tumors in many cases [68].

Clinical trials conducted by ADVAXIS on patients with metastatic carcinomas have also shown encouraging results, with tumor reduction observed in 30% of treated patients, although some side effects, such as hypotension and flu-like syndrome, were rapidly resolved by antibiotic and symptomatic treatment. In addition, Listeria monocytogenes has been explored as a vector for radiotherapy directed against breast cancers, offering a new therapeutic perspective for the treatment of metastases. Listeria monocytogenes is therefore proving to be a very promising candidate for both therapeutic and prophylactic applications in oncology, thanks to its ability to target tumor cells and induce a robust immune response [69].

Mycobacterium bovis

Mycobacterium bovis is a strain related to Koch's bacillus (BK) and is used in the BCG (Bacillus Calmette-Guérin) vaccine. This slow-growing curved bacillus is characterized by its resistance to acids and alcohols, identifiable by the Ziehl-Nielsen stain, which classifies it among the Acid-Fast Bacilli (AFB). It has a membrane composed of mycophenolic acid, is non-sporulated, immobile, and strictly aerobic. These characteristics differentiate it from other bacteria studied for their anticancer therapeutic potential [70].

Due to its strict requirement for oxygen, Mycobacterium bovis cannot grow in the hypoxic environments typical of internal tumor tissues, unlike other bacteria. However, this strain is particularly effective in the treatment of external tumors, mainly at the bladder level. The therapeutic strategy consists of directly inoculating the bacteria into the bladder through a urethral catheter. This inoculation provokes an intense immune response, marked by the production of numerous cytokines (IL-2, IL-6, IL-8, IL-10, IL-12, TNF-α, INF-α, and γ) and by the activation of several types of immune cells, including CD4, CD8 and NK cells. This response leads to targeted apoptosis of cancer cells, mainly induced by TNF-α (Figure 4) [71].

Attempts to reproduce this immune reaction by direct administration of cytokines have been made, but the presence of the bacteria seems essential to obtain an optimal response. In addition, the administration of cytokines with BCG improves the therapeutic efficacy compared to inoculation alone, although this can sometimes cause irritation and allergic reactions [71].

BCG therapy, used since its introduction by Morales in 1976, is today the reference treatment for bladder tumors at high risk of recurrence and progression. In clinical practice, BCG therapy is often used as adjuvant treatment after transurethral resection or as an adjunct to conventional chemotherapy. This approach significantly reduces recurrences and improves 5-year survival of patients [72].

In terms of protocols, induction treatment consists of weekly instillation for 6 weeks, followed by maintenance treatment. However, the protocols for this maintenance treatment are not standardized, and the dosage must sometimes be reduced to improve tolerance. The French Society of Urology recommends a complete assessment before installation, including a complete biological assessment [73].

Although BCG therapy is widely used with success, some aspects, such as the harmonization of protocols, could still be improved to optimize the tolerance and efficacy of the treatment. Nevertheless, Bacillus Calmette-Guérin remains a concrete example of the daily use of a bacterium to effectively treat bladder cancer, which is the sixth most common cancer in France [74].

Bifidobacterium spp.

Bifidobacterium is a genus belonging to the class Actinobacteria, characterized by Gram-positive, strictly anaerobic, non-sporulating, and nonmotile bacilli. These fermentative bacteria are mainly found in the mammalian colon and constitute an essential part of the human intestinal microbiota. Bifidobacterium is non-pathogenic and often used for its probiotic properties. Its fermentation produces lactic acid, lowering the pH and inhibiting the growth of other microorganisms. This ability is exploited in food preservation, particularly in fermented dairy products, although its main role remains oriented toward marketing applications. The therapeutic strategy using Bifidobacterium relies on its anaerobic character to target tumor tissues, particularly in hypoxic environments. Unlike other bacteria studied for their anticancer potential, Bifidobacterium is avirulent, meaning that it does not trigger inflammation or significant immune response, thus limiting its direct efficacy for tumor reduction. However, this feature makes it a potential vector for in situ drug or therapeutic agent delivery (Figure 5) [75].

An innovative application of this strategy is to use Bifidobacterium strains carrying a plasmid encoding Cytosine Deaminase (CD), a bacterial enzyme capable of converting the prodrug 5-fluorocytosine (5-FC) into 5-fluorouracil (5-FU), a potent anticancer agent. 5-FU, by inhibiting the metabolism of pyrimidine bases such as uracil, blocks the synthesis of nucleic acids, thus preventing tumor cell proliferation. By using Bifidobacterium to perform this conversion specifically at the tumor tissue level, this approach could significantly reduce the side effects associated with systemic 5-FU administration, while increasing the selectivity of treatment [76].

Preclinical studies in animal models, including tumor-bearing mice and rats, as well as toxicity tests in monkeys and guinea pigs, have not revealed any signs of significant toxicity or adverse reactions, suggesting that Bifidobacterium is a safe vector for this type of therapy. One of the major challenges remains industrial development, due to the large molecular size of this vector, which limits the delivery options, although oral administration is being considered [77].

Studies have shown that strains of Bifidobacterium breve, administered orally to mice, can migrate to tumors, where they multiply specifically without inducing toxicity or translocation of other bacterial populations. This targeted colonization of tumors seems promising, suggesting that Bifidobacterium could play a key role in the development of new therapeutic strategies against cancer [78, 79].

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