Over the past decade, scientists have learned that cancer is not driven by tumor cells alone. Disruptions in the gut microbiome have been linked to cancer development and progression through effects on genomic stability, immune evasion, and the tumor microenvironment.
At the same time, immunotherapies such as immune checkpoint inhibitors (ICIs) have transformed cancer care — but responses vary widely, with many patients showing primary or acquired resistance. Advances in sequencing technologies have revealed that gut microbial composition can influence who responds to immunotherapy, raising the possibility that the microbiome itself could be modified to improve outcomes.
Approaches such as fecal microbiota transplantation (FMT), diet, and targeted microbial therapies are now being explored as adjuvants to cancer treatment, opening the door to a new era of microbiome-based precision oncology.
In mice without gut bacteria, immunotherapies like anti-PD-1 or anti-CTLA-4 simply didn’t work — but the response could be restored with FMT or supplementation with beneficial bacteria.
—Arielle Elkrief, CHUM
Arielle Elkrief, a clinician-scientist at the Centre hospitalier de l’Université de Montréal (CHUM) and co-director of the CHUM Microbiome Centre, has been at the forefront of this research. “Scientists in 2015 and 2018 discovered that the gut microbiome was essential for the response to cancer immunotherapy,” she explained to DDN. “In mice without gut bacteria, immunotherapies like anti-PD-1 or anti-CTLA-4 simply didn’t work — but the response could be restored with FMT or supplementation with beneficial bacteria. We later observed that exposure to antibiotics led to worse survival in patients treated with immunotherapy. This led researchers to try to modify the gut microbiome to improve immunotherapy efficacy in the context of clinical trials.”
Building on these insights, Elkrief and her team designed the Phase 2 FMT-LUMINate trial, which tested whether transplanting healthy donor microbiomes could enhance immunotherapy response in patients with melanoma and non-small cell lung cancer (NSCLC).
The role of harmful bacteria
In the study, patients received a single FMT via oral capsules before starting ICI therapy. The donor selection process was meticulous: only healthy individuals with no prior medical conditions were accepted, and their stool and health status were screened thoroughly for infectious organisms by a dedicated team in London, Ontario.
Patients who received FMT experienced response rates far exceeding what is normally seen with immunotherapy alone. For example, in the NSCLC cohort, 80 percent of patients (16 of 20) experienced measurable tumor shrinkage when healthy donor FMT was given before anti-PD-1 therapy — substantially higher than the typical 39–45 percent expected with anti-PD-1 monotherapy. In the melanoma cohort, 75 percent (15 of 20) responded to a combination of FMT and dual checkpoint blockade (anti-PD-1 plus anti-CTLA-4), surpassing the usual 50–58 percent response rates historically seen with that regimen. These early outcomes suggest that reshaping the gut microbiome may be a powerful tool for helping patients overcome resistance to checkpoint inhibitors.
While the clinical results were impressive, Elkrief emphasized that understanding the mechanism of action is equally important. Her lab used shotgun metagenomics to further study the patients’ microbiome, discovering “that donor engraftment alone wasn’t enough to produce clinical responses.” She noted, “What appeared more important was the elimination of a patient’s own immunosuppressive gut microbiome.”
In the study, responders exhibited significantly greater loss of deleterious bacterial species compared to non-responders, with frequent depletion of Enterocloster citroniae, Enterocloster lavalensis, and Clostridium innocuum. “We observed that the loss of these harmful taxa led to the remodeling of immune cells, cytokine profiles, and systemic metabolic pathways, potentially enhancing the anti-tumor response,” said Elkrief.
To test whether the loss of harmful bacteria was driving patient responses, the researchers turned to mice. They first treated the animals with antibiotics to clear their native gut bacteria, then transplanted them with stool from patients who had responded well to FMT in the clinical trial. These mice showed enhanced responses to checkpoint inhibitors, mirroring the clinical results. Next, the team reintroduced specific deleterious bacteria that had been lost after FMT, and the therapeutic benefit diminished, confirming that removing these microbes was key.
Treatment across cancer types
The promise of microbiome modulation isn’t limited to melanoma and lung cancer. In a similar study published in Nature Medicine, researchers conducted the Phase 2 TACITO trial in patients with metastatic renal cell carcinoma, combining FMT with the immunotherapy agent pembrolizumab plus the targeted therapy axitinib.
Although this trial focused on a different cancer type and treatment regimen, early analyses of microbiome changes revealed outcomes similar to those seen in the FMT-LUMINate study — patients who received donor FMT showed significant shifts in gut microbial diversity and composition after treatment, and a greater loss of baseline species was associated with longer progression-free survival. These findings lend further support to the idea that alterations in the gut ecosystem may play a critical role across multiple cancer types and therapeutic combinations.
The potential implications are enormous. Beyond FMT, precision microbiome interventions could be tailored to individual patients, using computational models to predict which bacteria must be suppressed or encouraged for optimal immune responses. Such approaches could complement existing cancer therapies, transforming microbiome modulation from an experimental concept into a standard-of-care co-therapy.
However, translating these findings into widespread clinical practice is not without challenges. Administering FMT to a small group of patients is manageable, but scaling to larger trials — or routine use in hundreds or thousands of patients — introduces logistical and regulatory hurdles. Elkrief is now leading a larger randomized trial with 128 melanoma patients, known as the Canbiome2 trial, which aims to confirm and expand on the promising Phase 2 findings. While the early experience shows few logistical or safety challenges, the study is preparing to tackle the complexities of scaling microbiome therapies, including donor availability, and inter- and intra-donor variability.
A new era in oncology
The FMT-LUMINate and TACITO trial demonstrate that the microbiome is an active participant in shaping immune responses to tumors. By removing immunosuppressive bacteria and supporting beneficial microbial communities, researchers are discovering new ways to make immunotherapies more effective for patients who previously saw limited benefit.
With careful science, rigorous clinical trials, and innovative translational strategies, therapies like FMT could soon move from experimental interventions to routine tools in cancer care. Microbiome-based treatments could be combined with existing therapies, tailored to each patient’s unique microbial environment, and applied across a range of cancer types. Looking ahead, computational models and precision biotherapeutics may allow clinicians to design microbiome modifications that optimize immune responses, reduce side effects, and overcome treatment resistance — creating a new era of precision oncology guided by the microbiome.
