In recent years, immunotherapy has profoundly transformed the way we understand and treat cancer. Among the most revolutionary strategies are immune checkpoint inhibitors (ICIs), therapies that unlock the immune system and allow it to recognize and attack tumor cells. However, despite the enormous progress they represent, not all patients respond to this type of treatment. In fact, a significant proportion develops resistance, and many never benefit from it at all. This challenge has fueled an intense search for factors that influence the effectiveness of immunotherapy.

One of the most surprising discoveries of the last decade is that the gut microbiome, the collection of microorganisms living in our intestines, plays a fundamental role in the success or failure of immunological cancer treatment. This idea, which years ago might have seemed far-fetched, has been supported by multiple clinical and preclinical studies. So much so that researchers are now seriously exploring whether transplanting gut microbiota from healthy individuals could improve immunotherapy response in cancer patients. This procedure is known as fecal microbiota transplantation (FMT).

A new review published in Gut Microbes compiles the latest evidence and offers a critical look at the potential and the challenges of FMT to enhance the effectiveness of ICIs. The team led by Dr. Peng Luo from Southern Medical University evaluated various clinical trials in melanoma, colorectal cancer, and other solid tumors, and found results that are both promising and contradictory.

According to Dr. Luo, “the impact of FMT on the efficacy of immune checkpoint inhibitors varies dramatically across studies.” In some trials, the results are almost unbelievable: melanoma patients who had previously failed immunotherapy exhibited significant clinical responses after receiving FMT, with rates reaching 40%. This suggests that the gut microbiota alone could reactivate immune processes that had previously failed.

But the reality is not so simple. Other studies found that certain bacterial formulations not only failed to improve response but could even reduce treatment effectiveness compared to placebo. This duality reflects the enormous complexity of the human microbiome. We are not dealing with a conventional drug, but with a dynamic ecosystem composed of hundreds of bacterial species that interact with the immune system in ways that are still not fully understood.

 

One of the most important findings of the review is that the success of FMT depends on multiple factors. These include:

• Donor selection: Not all individuals possess a microbiome capable of enhancing immunotherapy. “Super-responder” donors, people whose microbiota promotes a highly active immune profile, appear to be key.
• Recipient characteristics: Each patient has a unique microbial composition, a distinct immune system, and a particular tumor type. All of this deeply influences how they respond to FMT.
• Specific bacterial communities transferred: Not all bacteria are equal. Some species can stimulate beneficial immune responses, while others can induce immunosuppressive cells that help tumors evade immune surveillance.

 

Dr. Luo highlights an especially striking observation: “What surprised us most was how the same bacterial species could have completely opposite effects in different patients.” This finding demonstrates that there is no universally beneficial microbiota for immunotherapy, and that even bacteria considered helpful in some contexts may be harmful in others. This opens the door to a more sophisticated approach: microbiome personalization.

But how exactly do gut bacteria influence the response to cancer treatment? The review points to several key mechanisms. Some bacteria can activate essential immune cells, such as cytotoxic T lymphocytes, which are critical for destroying tumor cells. Others can modify the tumor microenvironment, making it more permissive for immune activity. Conversely, certain microorganisms can promote the expansion of immunosuppressive cells, such as regulatory T cells or certain macrophage subsets, that inhibit immune responses and allow tumors to continue growing.

In this sense, the microbiome acts as an immunological switch that can tilt the balance toward or against therapeutic success. For this reason, targeting the microbiome has become an increasingly prominent area of research, with major clinical implications.

However, there are also significant risks and challenges. The microbiome is a highly delicate ecosystem. Altering it abruptly or using poorly studied bacterial combinations can lead to unpredictable effects. Some trials have reported gastrointestinal complications, infections, or even worsening of the cancer itself. This is why researchers emphasize the urgent need for large-scale clinical trials to clearly determine which protocols are safe, which bacteria should be used, and which patients are likely to benefit.

Another key recommendation from the review is the need to standardize FMT procedures. Currently, methods for collecting, processing, and administering microbiota vary widely among medical centers. This makes it difficult to compare results and identify which specific components are driving the observed effects. The creation of international guidelines could accelerate research and reduce risk, especially considering that we are working with complex biological material.

Figure 1. This figure illustrates the overall concept of fecal microbiota transplantation (FMT), showing how a donor’s healthy microbial community can replace a dysbiotic gut environment in the recipient. Through this shift, FMT has the potential to reshape immune function, promote stronger antitumor activity, and enhance the effectiveness of immune checkpoint inhibitors in cancer therapy.

The article also highlights the importance of developing predictive tools, meaning methods that can identify beforehand which patients are more likely to benefit from FMT. These might include microbiome analyses, immune profiling, or specific biomarkers. In the future, microbiota-based interventions may be integrated into clinical practice as part of personalized cancer treatment.

Despite the challenges, this area of research represents a crucial step forward in understanding the connection between the microbiome and immunotherapy. Being able to manipulate the microbiome to improve existing therapies opens a fascinating door to more precise, smarter, and potentially more effective medicine.

FMT is not yet a standard treatment, but the evidence suggests it could become a powerful tool to rescue patients who do not respond to ICIs and to amplify the effects of immunotherapy in various tumor types. Importantly, this strategy does not aim to replace current treatments, but to strengthen them, based on a revolutionary concept: that the microbes living in our gut can profoundly influence our ability to fight cancer.

Dr. Luo’s review not only examines what is already known but also outlines a path toward the future—a future in which the microbiome becomes an essential component of therapeutic design in oncology. With larger studies, standardized protocols, and a personalized focus, FMT could become one of the most important tools for improving clinical outcomes and offering new hope to patients with limited options.

Ultimately, we are witnessing the rise of a new era in which understanding and manipulating our microorganisms may be as essential as developing new drugs. And although there is still much to learn, what we already know is enough to imagine a future in which cancer is treated not only with chemistry and molecular biology, but also with the silent collaboration of the billions of microbes that live within us.

 

Main reference: 

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

 

Other references:

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

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