Exploring Fecal Microbiota Transplantation: Potential Benefits, Associated Risks, and Challenges in Cancer Treatment

Recent studies have demonstrated that FMT can significantly improve patient responses to ICIs, including anti‐PD‐1 and anti‐CTLA‐4 therapies [22]. Researchers have identified that patients with a gut microbiome enriched in Akkermansia muciniphila respond better to ICIs, suggesting that microbiota composition can influence treatment success [23]. Specific bacterial taxa, including Bifidobacterium longum , Faecalibacterium prausnitzii , and Ruminococcus species, have been associated with favorable immunotherapy responses [24]. FMT from responders to nonresponders has been shown to enhance immune activation and tumor regression in preclinical models and early‐phase clinical trials [25]. FMT may boost immunotherapy efficacy by enhancing antigen presentation and T‐cell activation, as shown in Figure 1. Increased SCFA production regulates immune responses. This reduces the levels of proinflammatory cytokines associated with therapy resistance [26].

Cancer treatments, such as chemotherapy, radiotherapy, and prolonged antibiotic use, significantly alter the gut microbiome, leading to dysbiosis [27]. This imbalance can cause systemic inflammation, compromise the gut barrier, and contribute to treatment‐related side effects [28]. FMT reintroduces beneficial microbial diversity and restores homeostasis [29]. The gut microbiota produces key metabolites, such as SCFAs, bile acids, and tryptophan derivatives, which influence host immunity and cancer progression [30]. FMT can replenish these critical metabolites, thereby modulating systemic inflammation and immune responses.

Chemotherapy and radiotherapy often lead to severe gastrointestinal side effects, including diarrhea, mucositis, and colitis [31]. FMT has been reported to alleviate these symptoms by restoring beneficial microbial populations and improving gut barrier integrity [32]. Clinical trials are currently investigating FMT as a treatment for immune‐related colitis in patients treated with ICIs. Cancer cachexia, characterized by severe weight loss and muscle wasting, has been linked to gut dysbiosis [33]. Certain gut microbiota compositions promote systemic inflammation via the production of LPS and proinflammatory cytokines (IL‐6 and TNF‐α) [34]. FMT has shown promise in modulating metabolic pathways, reducing systemic inflammation, and potentially alleviating cachexia‐related symptoms [35]. FMT is a promising therapeutic approach for improving cancer treatment outcomes, particularly by enhancing the immunotherapy response, restoring gut microbiome balance, and mitigating cancer‐related complications [36]. However, large‐scale clinical trials are necessary to establish standardized protocols, assess long‐term safety, and optimize patient selection for FMT interventions in oncology.

Although microbial taxa such as Akkermansia muciniphila , Faecalibacterium prausnitzii , and Bacteroides fragilis have been associated with improved ICI responses, their causality remains debatable. Many correlations may reflect an underlying immunological or metabolic state, rather than a direct microbial effect. For instance, the enrichment of A. muciniphila may indicate intact mucosal integrity or reduced antibiotic exposure, both of which are associated with better therapeutic response. Similarly, SCFAs, such as butyrate, exert pleiotropic effects, being anti‐inflammatory in some settings but protumorigenic in others by promoting regulatory T cells' expansion. Future research should integrate multiomics profiling (metabolomics and single‐cell immune mapping) and causality frameworks (gnotobiotic validation and microbial knockout models) to delineate the mechanistic hierarchies. Understanding whether these taxa drive or merely accompany favorable immune landscapes is crucial for the development of precision FMT.

Despite rigorous donor screening, there is always a risk of undetected pathogens being transferred through FMT [39]. Bacterial, viral, fungal, and parasitic infections may be transmitted, posing a significant threat to immunocompromised cancer patients. Cases of Escherichia coli bacteremia and Clostridium difficile reinfection have been reported following FMT in immunocompromised patients [40]. Viral infections, including those caused by latent viruses such as cytomegalovirus (CMV) and Epstein–Barr virus (EBV), could theoretically be reactivated following FMT, although data on this are limited [41]. Similarly, FMT has been linked to the transmission of extended‐spectrum beta‐lactamase (ESBL)‐producing Enterobacteriaceae, a group of antibiotic resistant bacteria [42]. Patients with cancer who are already at risk of hospital‐acquired infections may experience worsened outcomes if resistant organisms colonize the gut following FMT. Despite its therapeutic potential, FMT is associated with several clinical and biosafety risks. Common short‐term adverse events include abdominal discomfort, flatulence, nausea, and mild diarrhea, which are generally self‐limiting. However, although rare, severe complications have been reported, such as Enterobacteriaceae or Enterococcus bacteremia in immunocompromised recipients and aspiration pneumonia during colonoscopic or nasojejunal administration [43]. The US FDA has also documented cases of transmission of multidrug‐resistant organisms (MDROs) and latent viral infections via inadequately screened donor stools. In addition to the risk of infection, FMT may cause unintended long‐term consequences, including the horizontal transfer of antimicrobial resistance genes, alterations in bile acid metabolism, and the potential promotion of oncogenic pathways in predisposed individuals. Immunological risks also persist because the donor microbiota may elicit unpredictable immune responses or interfere with checkpoint blockade therapy. Consequently, rigorous donor screening, standardized manufacturing, and long‐term follow‐up are indispensable to mitigate these risks and ensure safe clinical translation in oncology.

FMT may induce immune activation, which can trigger or worsen autoimmune disorders, particularly in patients with cancer and pre‐existing immune dysfunction [44]. Inflammatory cytokines, such as IL‐6 and TNF‐α, can be upregulated, leading to immune‐related adverse events [44]. In another study, hematopoietic stem cell transplant (HSCT) recipients were found to be particularly vulnerable, as FMT could stimulate immune responses that exacerbate graft‐versus‐host disease (GVHD) [45]. Under these conditions, donor immune cells attack the recipient tissues. Cases of severe colitis and systemic inflammation have been observed following FMT in transplant recipients.

Although FMT aims to restore the microbiome balance, unintended shifts in microbial populations can have negative effects. Overgrowth of certain bacterial species, such as Enterococcus faecalis and Klebsiella pneumoniae , may disrupt gut homeostasis and cause inflammation [46]. Similarly, the effect of introducing a completely new microbial ecosystem into cancer patients remains poorly understood. Some studies have shown that long‐term changes in the microbiome following FMT may influence metabolism, immune function, and mental health [47].

Some gut bacteria have been implicated in tumorigenesis, raising concerns that FMT could inadvertently introduce procarcinogenic species. Fusobacterium nucleatum , which promotes colorectal cancer progression, has been found to be more abundant in some post‐FMT cases [48]. Certain bacterial metabolites, such as secondary bile acids and reactive nitrogen species, have been linked to DNA damage and an increased risk of cancer [49]. Long‐term oncogenic risks associated with gut microbiome alterations induced by FMT remain an area of active research.

To minimize the risks associated with FMT in patients with cancer, the following strategies should be employed: stringent donor screening and comprehensive screening for pathogens, antimicrobial resistance genes, and potentially harmful microbial strains before FMT [50]. Personalized microbiome selection using metagenomic analysis to select donor microbiomes tailored to the recipient's specific needs could improve safety and efficacy. Synthetic and next‐generation FMT, such as advancements in microbiome engineering, defined microbial consortia, and stool‐derived microbial products, may offer safer alternatives to traditional FMT [51]. Therefore, long‐term monitoring is required. Post‐FMT surveillance should include microbiome profiling, immune response assessment, and monitoring of cancer progression. Although FMT holds promise as a novel therapeutic approach for cancer treatment, the potential risks must be carefully considered, particularly in immunocompromised patients. Future research should focus on refining the donor selection criteria, developing safer microbiome‐based therapies, and elucidating the long‐term consequences of microbiota modulation in patients with cancer. Reported adverse events following FMT include transient gastrointestinal discomfort (abdominal cramping, bloating, and flatulence), mild fever, and self‐limited diarrhea [52]. Rare but severe complications, such as bacteremia, aspiration during colonoscopic administration, and exacerbation of inflammatory bowel disease, have also been documented. In immunocompromised patients, opportunistic infections caused by multidrug‐resistant E. coli or Enterococcus species have been reported, underscoring the need for vigilant monitoring and robust infection control protocols [53]. Overall, the incidence of serious adverse events remains below 5% in most controlled studies, suggesting that FMT is generally safe when patients are appropriately screened and monitored.

One of the primary challenges of FMT is ensuring that donor microbiomes are safe and beneficial for patients with cancer, particularly those with compromised immune systems. Figure 2 shows the screening factors for FMT. Despite rigorous screening, undetected pathogens in donor stool pose a significant risk, particularly in immunosuppressed patients undergoing chemotherapy or immune checkpoint inhibition [55]. Cases of multidrug‐resistant E. coli transmission via FMT have been reported, underscoring the need for enhanced screening protocols [40]. Not all microbiomes are beneficial for every cancer patient; an FMT that benefits one individual may have neutral or even adverse effects on another [56]. Studies suggest that specific bacterial taxa, such as Bacteroides fragilis and Faecalibacterium prausnitzii , may enhance immunotherapy responses, whereas other strains may exacerbate inflammatory conditions [23]. The concept of a “universal” microbiome donor, similar to universal blood donors, is still under investigation [57]. The current study aimed to identify the microbial composition that maximizes FMT efficacy while minimizing risks. One of the key challenges in donor screening is the detection of asymptomatic carriers of pathogens such as Enterobacteriaceae, Clostridioides difficile, Campylobacter, and enteric viruses (e.g., norovirus and adenovirus). Clinically healthy donors may harbor antimicrobial resistance genes or latent viral infections that evade standard diagnostic assays. Studies have indicated that only 10%–15% of potential donors typically qualify after complete screening, which includes medical history, serological testing, stool pathogen screening, and antibiotic resistance profiling [58]. This low qualification rate underscores the difficulty of maintaining consistent donor availability and highlights the need for synthetic, donor‐independent alternatives.

The clinical use of FMT in oncology is hindered by the lack of standardized protocols and the need for personalized approaches [36]. FMT can be delivered in different forms, including fresh stool, frozen stool, encapsulated formulations, and lyophilized powders [59]. The efficacy of these different preparations in cancer patients remains poorly understood, and there is no consensus on the best method of administration. Patients with cancer exhibit significant heterogeneity in their gut microbiome composition. Current FMT practices often do not consider individual microbiome profiles, which leads to variable responses. The optimal frequency, dosage, and timing of FMT relative to cancer treatments, such as immunotherapy, remain unclear [60]. Overdosing or inappropriate timing may result in transient dysbiosis rather than long‐term microbiome restoration.

However, FMT is not yet fully regulated as a cancer therapy, which creates uncertainty about its clinical applications. In many countries, FMT is only approved for recurrent Clostridium difficile infections and is not formally recognized as a treatment for cancer‐related microbiome imbalance [54]. Regulatory agencies, including the Food and Drug Administration (FDA), categorize FMT as an investigational drug, limiting its widespread clinical application [61]. In patients with late‐stage cancer, experimental treatments such as FMT must balance potential benefits with unknown risks. Informed consent is challenging, especially given the limited long‐term safety data on FMT in oncology. Stool banking and FMT access are currently limited to a few specialized centers, making the therapy inaccessible to many cancer patients [62]. Ethical concerns have arisen regarding the commercialization of human stool for therapeutic use.

Although FMT has shown promise in modulating immune responses and improving treatment outcomes, significant gaps remain in our understanding of its precise mechanisms in cancer care. The interactions among FMT, gut microbiota, and the TME remain poorly understood [63]. While some studies suggest that FMT can enhance antitumor immunity, others indicate that microbial shifts can promote tumor growth under certain conditions [64]. The interaction between FMT‐derived microbes and the host immune system, metabolism, and systemic inflammation remains an active area of research [65]. However, the long‐term effects of microbiome modification on cancer progression and recurrence remain unknown. While FMT enhances the response to ICIs, its interactions with other cancer treatments, such as chemotherapy and radiotherapy, require further investigation [66]. Certain bacterial metabolites, such as bile acids and tryptophan derivatives, may influence drug metabolism and toxicity, necessitating caution in their clinical application [67]. Despite its potential in cancer care, FMT faces several implementation challenges, including donor screening limitations, lack of personalization, regulatory hurdles, and incomplete mechanistic understanding [62]. Addressing these barriers will require rigorous clinical trials, refined microbial selection techniques, and standardized protocols to ensure the safety and efficacy of FMT in oncology patients. With advances in research, next‐generation microbiome‐based therapies, such as defined microbial consortia and engineered probiotics, may provide more controlled and targeted alternatives to traditional FMT.

A study showed that FMT from melanoma patients who responded well to anti‐PD‐1 therapy, when administered to germ‐free or antibiotic treated mice, improved their response to ICIs [5]. The study revealed that beneficial microbial species, such as Akkermansia muciniphila and Bifidobacterium spp., promote T‐cell infiltration into tumors and enhance antitumor immunity. In addition to Akkermansia and Faecalibacterium, Bacteroides species are major components of transplanted microbial communities [68]. Studies have indicated that Bacteroides fragilis and Bacteroides thetaiotaomicron enhance antitumor immunity by producing polysaccharide A, which modulates dendritic cell maturation and promotes Th1 immune responses [69]. Moreover, the Bacteroides genus has been shown to restore gut homeostasis following chemotherapy‐induced dysbiosis, although excessive abundance may also drive inflammation in some contexts [70]. Thus, including and regulating Bacteroides populations during FMT is critical for balancing therapeutic efficacy and safety.

Another study has demonstrated that gut microbiota plays a crucial role in modulating responses to chemotherapy. Mice treated with broad‐spectrum antibiotics showed impaired responses to cyclophosphamide, suggesting that microbe‐derived metabolites contribute to immune activation [71]. Similar findings have been reported for radiotherapy, in which microbial diversity influences radiation‐induced inflammation and DNA damage repair.

While FMT has been shown to enhance antitumor immunity, some studies have suggested that an inappropriate microbiome shift can promote tumorigenesis [72]. Researchers have found that Fusobacterium nucleatum transferred via FMT accelerates colorectal cancer growth by suppressing immune responses and promoting chemoresistance [73]. These findings underscore the need for the precise selection of microbes in FMT protocols to avoid the introduction of tumor‐promoting bacteria. The translation of FMT into clinical oncology is still in its early stages; however, multiple trials are investigating its safety and efficacy in various cancers, particularly when it is combined with immunotherapy.

Emerging evidence indicates that FMT can reprogram the tumor TME by restoring microbial homeostasis and reshaping host immune dynamics. FMT introduces a balanced consortium of commensal microbes that enhance antigen presentation, stimulate dendritic cell maturation, and increase cytotoxic CD8⁺ T cell infiltration within the TME. These changes counteract immunosuppressive signaling, reduce regulatory T cell activity, and downregulate inhibitory checkpoints, such as PD‐L1 expression. Additionally, microbe‐derived metabolites, including butyrate and propionate, modulate epigenetic regulation and cytokine profiles, promoting an anti‐inflammatory yet immunostimulatory milieu that favors tumor suppression. Such immune reprogramming not only potentiates the efficacy of ICIs but also improves treatment tolerance and reduces therapy‐induced mucosal injury. In the context of therapy, the gut microbiome significantly affects the efficacy and toxicity of anticancer treatment. During chemotherapy and radiotherapy, microbial composition determines the host's drug metabolism and susceptibility to mucositis and systemic inflammation. Certain microbial enzymes metabolize chemotherapeutic agents, thereby altering their bioavailability and pharmacodynamics. Furthermore, a healthy gut ecosystem is essential for maintaining intestinal integrity, which is frequently compromised during cytotoxic treatment and predisposes patients to infections and inflammation.

These studies suggest that FMT helps overcome resistance to ICIs by restoring beneficial microbial taxa associated with antitumor immunity (Table 1).

Recent Phase I/II studies have begun to translate FMT into oncological settings, particularly for restoring responsiveness to ICIs. Studies have demonstrated that FMT from ICI responders induces objective responses in 20%–30% of previously refractory melanoma patients, accompanied by the expansion of cytotoxic CD8⁺ T cells and decreased infiltration of myeloid suppressor cells [79]. However, these small, nonrandomized trials (n = 10–15 per arm) were limited by donor variability, short follow‐up (< 12 months), and a lack of mechanistic biomarkers predictive of sustained benefit. In contrast, studies on metastatic renal cell carcinoma [80] and NSCLC have shown transient immune activation without a significant clinical response, suggesting that tumor type, antibiotic exposure, and baseline microbiome composition influence therapeutic outcomes [81]. Collectively, early phase trials have provided encouraging yet heterogeneous results, underscoring the urgent need for randomized, donor‐matched, and longitudinally monitored FMT studies to validate its reproducibility and safety in cancer cohorts.

Several clinical trials are currently being conducted to investigate the role of FMT in cancer treatment. The first trial focused on FMT and immunotherapy synergy (Clinical Trial: NCT04130763↗) [82], in which the evaluation aimed to determine whether FMT from ICI responders can improve immunotherapy outcomes in melanoma patients who have failed initial anti‐PD‐1 therapy. Another clinical trial examined the potential of FMT to counteract antibiotic induced dysbiosis in patients with cancer (Clinical Trial: NCT04264975↗) [83], specifically investigating whether FMT can restore gut microbiome balance in patients with lung cancer who received antibiotics before immunotherapy. Finally, research is being conducted on FMT for preventing chemotherapy‐induced toxicity (Clinical Trial: NCT04577729↗) [84], assessing whether it can reduce chemotherapy‐induced diarrhea and gut inflammation in patients with colorectal cancer.

Despite these promising results, several challenges remain in the translation of FMT into routine cancer therapy. The lack of standardization in donor selection and microbial composition makes it difficult to replicate the results across different studies [58]. However, long‐term safety concerns, particularly those related to the introduction of tumor‐promoting bacteria, require further evaluation. Regulatory hurdles remain, as FMT is currently only approved for recurrent Clostridium difficile infections in many countries [85]. The next step is to develop defined microbial consortia rather than whole‐stool FMT to ensure safety and precision. Large‐scale randomized controlled trials are recommended to confirm the efficacy and long‐term benefits of this treatment for various types of cancer. Exploring engineered probiotics and postbiotics as alternatives to traditional FMT [86]. Emerging evidence from preclinical and early phase clinical trials suggests that FMT holds promise for enhancing cancer treatment outcomes, particularly through immunotherapy. However, rigorous research is still needed to standardize FMT protocols, identify optimal microbial compositions, and evaluate the long‐term safety of FMT in patients with cancer. As research advances, FMT may become a key tool in microbiome‐based precision medicine for oncology.

Despite its promise, FMT carries inherent risks, including pathogen transmission and unintended alterations to the microbiome. Future innovations will aim to improve the safety, reproducibility, and regulatory approval of clinical use. Traditional FMT relies on donor stool and requires rigorous screening for bacterial, viral, and parasitic infections. However, rare cases of multidrug‐resistant bacterial transmission have raised concerns [93]. New techniques, such as metagenomic sequencing, enable more precise donor screening by analyzing the complete microbial composition of stool samples. Standardized stool banks have been established to ensure high‐quality and consistent FMT materials [94]. Some initiatives are working to create a library of well‐characterized FMT donors to enable better donor matching based on patient microbiome profiles. Researchers are currently investigating synthetic microbiomes that are free of potential pathogens and unwanted bacteria. CRISPR‐based approaches allow the selective removal of harmful bacteria from FMT preparations before transplantation.

One major challenge in FMT research is that not all cancer patients respond equally to treatment. Identifying biomarkers could help predict who will benefit from FMT and guide personalized microbiome‐based interventions.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.