Fecal microbiota transplantation as a therapeutic adjuvant in gastrointestinal cancers: potential mechanisms, therapeutic applications, and a functional donor screening strategy

Gastrointestinal (GI) cancers account for approximately one‑third of cancer‑related deaths worldwide, and outcomes remain poor despite advances in surgery, chemotherapy, radiotherapy, and immunotherapy. Gut microbiota and fecal microbiota transplantation (FMT) are increasingly recognized as potential therapeutic adjuvants. FMT may enhance antitumor efficacy and reduce treatment‑related toxicity by improving antigen presentation, reshaping the tumor microenvironment (TME), and preserving intestinal barrier function. Early clinical evidence suggests that FMT combined with immune checkpoint inhibitors (ICIs), chemotherapy, or radiotherapy may improve response rates and alleviate toxicity in selected patients. However, donor microbiota heterogeneity, unpredictable engraftment, and lack of validated predictive models hinder clinical translation. This review proposes a functional donor screening framework—the Healthy Donor‑derived Microbiota Xenograft (HDMX) model and its clinical application, XenoFMT—to advance FMT toward precision intervention.

Introduction

GI cancers remain among the most lethal malignancies. Acquired resistance and treatment‑related toxicities are persistent challenges. Gut dysbiosis is linked to GI cancer initiation, progression, and prognosis, and also influences immunotherapy efficacy and toxicity. FMT, which transfers fecal material from healthy donors to reconstruct the recipient gut ecosystem, has shown success in recurrent Clostridioides difficile infection. Its translation to GI oncology is still early, but preliminary studies suggest potential as an adjuvant to ICIs, chemotherapy, and radiotherapy.

Potential Mechanisms

FMT may enhance antitumor immunity through three interconnected mechanisms. First, it can enhance antigen presentation by modulating dendritic cell (DC) activation and maturation, promoting T‑cell priming. Specific commensals and microbial metabolites can influence DC function, although effects are context‑dependent. Molecular mimicry between microbial and tumor epitopes may also prime cross‑reactive T cells. Second, FMT can reshape the TME by increasing intratumoral CD8⁺ T‑cell infiltration, reducing regulatory T cells and myeloid‑derived suppressor cells, and reprogramming tumor‑associated macrophages toward immunostimulatory phenotypes. Microbial metabolites such as short‑chain fatty acids, bile acids, and inosine may mediate these effects. Third, FMT can preserve intestinal barrier function by restoring tight junction proteins, mucus secretion, and epithelial repair, thereby reducing bacterial translocation and systemic inflammation.

FMT Combined with ICIs

ICI resistance is multifactorial, and gut dysbiosis contributes to systemic immune dysfunction. Preclinical studies show that FMT from ICI responders can restore antitumor immunity and potentiate ICIs. In melanoma, responder‑derived FMT has resensitized refractory patients, and healthy‑donor FMT combined with anti‑PD‑1 achieved an objective response rate of 65% in a phase I trial. In GI cancers, early‑phase studies report disease control rates of 40–95% in heterogeneous cohorts, including colorectal, gastric, esophageal, and hepatocellular carcinoma. However, these studies are small, non‑randomized, and lack long‑term safety data.

FMT Combined with Chemotherapy and Radiotherapy

Preclinical evidence suggests FMT can enhance chemotherapy efficacy and mitigate chemotherapy‑induced intestinal injury by restoring microbial diversity, butyrate‑producing commensals, and barrier integrity. Clinical data remain limited; a small trial in cachectic gastroesophageal cancer patients showed improved disease control with allogenic FMT before chemotherapy. For radiotherapy, FMT may protect against radiation‑induced enteritis by restoring goblet cells, mucus layer, and tight junctions. Clinical evidence is largely limited to case reports and small series in gynecological cancers, with symptomatic improvement in chronic radiation enteritis.

HDMX‑Based Donor Screening for XenoFMT

Current donor selection relies mainly on safety screening and taxonomic profiling, which are insufficient to predict therapeutic efficacy. The authors propose the HDMX model: transplanting microbiota from individual donors into microbiota‑depleted mice, followed by tumor inoculation and therapy, to functionally screen donor microbiota. Validated donors are then used clinically in XenoFMT, linking preclinical functional validation with personalized microbiota delivery. This framework aims to move FMT from empirical intervention toward precision adjuvant therapy.

Safety Concerns

FMT is generally safe but carries risks, especially in immunocompromised oncology patients. Pathogen transmission has been reported, including ESBL‑producing E. coli, Shiga toxin‑producing E. coli, and norovirus. FMT may also introduce microbial taxa or metabolites that attenuate antitumor immunity, and interactions with ICIs, chemotherapy, or radiotherapy remain unpredictable. Safety reporting in oncology trials is limited, and long‑term surveillance is needed.

Limitations

Most clinical evidence comes from early‑phase, single‑arm studies and small cohorts. Large randomized controlled trials in GI cancers are lacking. Donor sources, cancer subtypes, and combination regimens are heterogeneous, and microbial engraftment is variable. Many mechanistic insights are extrapolated from murine models. The HDMX‑XenoFMT framework is theoretical and not clinically validated. Evidence is uneven across GI cancer subtypes.

Conclusions

FMT is a promising adjuvant in GI oncology, with potential to enhance antitumor efficacy and reduce treatment‑related toxicity through antigen presentation, TME modulation, and barrier preservation. The proposed HDMX‑XenoFMT pipeline may advance FMT toward precision intervention. However, clinical translation requires prospective validation, large randomized trials, long‑term safety surveillance, and multi‑omics integration to establish FMT as a validated precision adjuvant in GI oncology.

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https://www.xiahepublishing.com/2835-3315/CSP-2026-00033

The study was recently published in the Cancer Screening and Prevention.

Cancer Screening and Prevention (CSP) publishes high-quality research and review articles related to cancer screening and prevention. It aims to provide a platform for studies that develop innovative and creative strategies and precise models for screening, early detection, and prevention of various cancers. Studies on the integration of precision cancer prevention multiomics where cancer screening, early detection and prevention regimens can precisely reflect the risk of cancer from dissected genomic and environmental parameters are particularly welcome.

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