For many years, it was believed that the bacteria living in our intestine were only involved in digestion. However, in recent years, science has revealed a much more complex and fascinating picture: these microorganisms are also in constant communication with the immune system and influence processes that extend far beyond the digestive tract. Today, we know that the so-called gut microbiota may play an important role in metabolic diseases, neurological disorders, autoimmune diseases, and even cancer.
This discovery has opened one of the most promising areas of research in modern medicine. Numerous studies suggest that the composition of the gut microbiota may influence the body’s ability to recognize and fight tumor cells, as well as the effectiveness of certain immunotherapy treatments. Although many questions remain unanswered, the available evidence suggests that the gut could become an unexpected ally in the fight against cancer.
The Gut: A much more important organ than we once imagined
The gastrointestinal tract is home to trillions of microorganisms—including bacteria, viruses, and fungi—that coexist in balance with our bodies. Far from being simple passengers, these microorganisms perform essential functions such as nutrient digestion, vitamin production, and protection against potentially harmful microbes.
Perhaps one of their most important roles is their close relationship with the immune system. It is estimated that between 60% and 80% of the body’s immune cells are associated with the gut, where they continuously learn to distinguish between real threats and harmless substances. This constant interaction helps maintain a delicate balance between activating immune defenses when needed and preventing excessive inflammatory responses.
When this balance is disrupted—a condition known as intestinal dysbiosis—changes can occur that promote chronic inflammation, weaken the intestinal barrier, and alter the way the immune system responds to different diseases, including cancer. For this reason, many researchers now believe that the gut microbiota not only reflects overall health but also actively participates in regulating it.
What does this have to do with immunotherapy?
Immunotherapy has revolutionized cancer treatment by helping the immune system recognize and attack tumor cells. Drugs such as immune checkpoint inhibitors have produced long-lasting responses in some patients with melanoma, lung cancer, kidney cancer, and several other malignancies.
However, one major challenge remains: not every patient responds in the same way. While some experience remarkable tumor shrinkage, others obtain only limited benefits—or fail to respond altogether.
Over the past few years, numerous studies have identified a possible explanation for part of this variability: the composition of the gut microbiota. Some patients harbor bacterial communities that appear to promote a stronger immune response, whereas others have microbial profiles associated with less favorable outcomes. This has led researchers to consider the gut microbiota as a potential biomarker capable of predicting future responses to immunotherapy.
A constant conversation between bacteria and immune cells
Gut bacteria do not remain isolated within the intestine. Through a wide variety of chemical signals and molecules produced during their metabolism, they maintain continuous communication with different immune cell populations.
For example, some bacteria promote the maturation of dendritic cells, which present tumor fragments to T cells to initiate an effective immune response. Others influence macrophages, immune cells capable of eliminating microorganisms and coordinating inflammation. They can also modulate the activity of CD8⁺ T cells, one of the immune system’s primary “armies” responsible for destroying cancer cells.
This complex communication network helps determine whether the immune system will remain relatively passive toward a tumor or mount a stronger response capable of enhancing the effectiveness of immunotherapy.
Not all bacteria have the same effects
One of the most interesting discoveries is that different bacterial species appear to perform very different functions.
Some bacteria belonging to the Bifidobacterium genus have been associated with improved dendritic cell activation and enhanced T-cell responses against cancer. Others, such as Akkermansia muciniphila, have attracted considerable attention because several studies have linked them to better clinical responses to PD-1 inhibitors.
Beneficial microorganisms belonging to the Lactobacillus, Faecalibacterium, and Enterococcus genera have also been associated with a more favorable immune microenvironment for fighting tumors. Nevertheless, the authors emphasize that these findings are not yet universal and that their effects may vary depending on the type of cancer, the individual patient, and other environmental factors.
The invisible molecules produced by gut bacteria
Perhaps bacteria themselves are not the real protagonists, but rather the molecules they produce.
As they metabolize food—particularly dietary fiber and other nutrients—they generate compounds known as microbial metabolites. These small molecules can cross the intestinal barrier, enter the bloodstream, and influence tissues located far beyond the gut.
Among the best-studied microbial metabolites are the short-chain fatty acids (SCFAs), including butyrate, acetate, and propionate. These molecules help maintain intestinal barrier integrity, regulate inflammatory processes, and contribute to the activation of various immune cell populations. Some studies have even found that patients with higher concentrations of these metabolites experienced longer progression-free survival during treatment with PD-1 inhibitors.
In addition to SCFAs, molecules such as inosine, certain tryptophan derivatives, bacteria-modified bile acids, and TMAO also appear to influence the activity of T cells, NK cells, macrophages, and other immune populations involved in antitumor responses. Although the underlying mechanisms are still under investigation, these discoveries demonstrate that the gut microbiota communicates with the immune system through an intricate network of biochemical signals.
Can we modify the gut microbiota to improve cancer treatment?
If certain bacteria promote stronger immune responses, an inevitable question arises: is it possible to modify the gut microbiota to increase the effectiveness of immunotherapy?
Today, this is one of the most active areas of research in oncology. Scientists are exploring different strategies aimed at creating an intestinal ecosystem that supports a more effective immune response against cancer. These approaches include the use of probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation (FMT). Although all of these strategies are promising, none has yet become part of standard clinical practice for enhancing immunotherapy.
Probiotics: Much more than “Good Bacteria”
Probiotics are commonly associated with supplements designed to improve digestive health. However, in the context of cancer, the situation is much more complex.
Some studies have shown that specific species of Lactobacillus, Bifidobacterium, Faecalibacterium, and Akkermansia may promote a more active immune environment and enhance responses to certain immunotherapies. On the other hand, other studies have reported less encouraging results and even suggest that some commercially available probiotic supplements may provide little benefit or, depending on the context, interfere with immune responses. This apparent contradiction highlights that not all probiotics are the same and that each bacterial strain may have distinct biological effects. Consequently, researchers emphasize the need to develop well-characterized formulations supported by rigorous clinical trials before recommending their use in cancer patients.
Diet can also influence the gut microbiota
Diet is one of the major factors shaping the composition of the gut microbiota. What we eat every day determines which microorganisms thrive and which decline, indirectly influencing the production of microbial metabolites capable of regulating immune function.
Several studies suggest that a fiber-rich diet promotes the production of short-chain fatty acids, molecules that help maintain intestinal barrier integrity and regulate inflammation. In addition, some evidence indicates that adequate intake of dietary fiber and omega-3 fatty acids may be associated with improved responses to immunotherapy.
The review also discusses research investigating the impact of the ketogenic diet on both the tumor microenvironment and the gut microbiota. Although some experimental findings are promising, the authors stress that there is currently insufficient evidence to recommend this dietary intervention as a general adjunct to immunotherapy. Its effects are likely to depend on the type of cancer, the patient’s metabolic status, and other individual factors.
Fecal Microbiota Transplantation: A strategy generating great interest
Among all the approaches currently under investigation, one of the most intriguing is fecal microbiota transplantation (FMT). This procedure involves transferring intestinal microorganisms from a healthy donor—or from a patient who responded well to treatment—to another individual in order to restore a healthier microbial ecosystem.
Although it may sound like a novel concept, FMT has already been successfully used to treat recurrent intestinal infections. Researchers are now investigating whether it can also help patients who initially fail to respond to immunotherapy.
Early clinical trials in melanoma have produced encouraging results. In some patients who were resistant to PD-1 inhibitors, FMT partially restored treatment responsiveness, and in certain cases tumor shrinkage was observed. Researchers also reported favorable changes in both the intestinal microbiota and the activity of immune cells within the tumor microenvironment.
Nevertheless, significant challenges remain. Transplanted bacteria do not always establish long-term colonization within the recipient’s intestine. Factors such as immune status, intestinal barrier integrity, previous diet, and antibiotic exposure can all influence the success of the procedure. Therefore, larger clinical studies are still needed to determine which patients are most likely to benefit from this strategy.
Figure 1. Overview of microbiota-derived metabolites and microbiome-based strategies that may enhance cancer immunotherapy.
Can the gut microbiota reduce immunotherapy side effects?
Immunotherapy has transformed cancer treatment, but it can also produce side effects caused by excessive activation of the immune system. These immune-related adverse events may affect organs such as the intestine, skin, liver, and endocrine glands.
In this context, the gut microbiota has once again emerged as a key area of interest. Several studies have observed that patients who develop these side effects often display a distinct gut microbial composition even before treatment begins. Beneficial bacteria such as Bifidobacterium, Faecalibacterium prausnitzii, and certain Lactobacillus species are frequently found at lower levels in these patients.
Although microbiota-based therapies specifically designed to prevent these adverse events are not yet available, these findings raise the possibility that, in the future, the gut microbiome could help identify patients at greater risk and support the development of more personalized preventive strategies.
Many questions still remain
Despite the tremendous excitement surrounding this field, researchers remain cautious. The gut microbiota is extraordinarily complex, and every individual harbors a unique microbial community influenced by genetics, age, diet, environment, medications, and lifestyle.
Furthermore, it remains unclear whether there is an “ideal microbiota” that applies across all cancer types or whether each tumor requires a distinct microbial profile. Even some microbial metabolites that appear beneficial in certain studies have produced contradictory findings in others, highlighting the need for further investigation into the underlying biological mechanisms. Technical challenges related to sequencing standardization, data interpretation, and reproducibility between studies also remain significant.
A future where the gut becomes part of cancer treatment
Research on the gut microbiota is transforming our understanding of the relationship between the human body and cancer. What was once considered merely a collection of microorganisms involved in digestion is now emerging as an important factor capable of influencing immune responses, the effectiveness of immunotherapy, and even the development of treatment-related side effects.
Although we are not yet at the point where the gut microbiota can be routinely used as a clinical tool for every patient, the progress made over the past few years has been remarkable. Strategies based on personalized microbiomes, microbial metabolites, targeted dietary interventions, and fecal microbiota transplantation could usher in a new era of precision oncology.
Ultimately, a better understanding of the ongoing dialogue between gut bacteria and the immune system will not only help explain why some patients respond better to immunotherapy than others, but may also contribute to the development of safer, more effective, and increasingly personalized cancer treatments. In the future, the fight against cancer may depend not only on the characteristics of the tumor or the immune system, but also on the complex microscopic ecosystem living within our intestines.
Main reference:
Jia, Y., Liu, Y., & Liu, J. (2026). The relationship between gut microbiota and cancer immune response and immunotherapy. Frontiers in immunology, 17, 1833138. https://doi.org/10.3389/fimmu.2026.1833138
Other references:
Mattavelli, E., Da Prat, V., Corallo, S., Tartara, A., Figini, S., De Simeis, F., Marino, S., Uggè, A., Caccialanza, R., Pedrazzoli, P., & Lasagna, A. (2026). Harnessing the gut microbiota in extra-intestinal cancers: from causal evidence to immunotherapy strategies. Immunotherapy, 18(3), 223–235. https://doi.org/10.1080/1750743X.2026.2648431
Lin, A., Jiang, A., Huang, L., Li, Y., Zhang, C., Zhu, L., Mou, W., Liu, Z., Zhang, J., Cheng, Q., Wei, T., & Luo, P. (2025). From chaos to order: optimizing fecal microbiota transplantation for enhanced immune checkpoint inhibitors efficacy. Gut microbes, 17(1), 2452277. https://doi.org/10.1080/19490976.2025.2452277
