One of the most promising areas of modern cancer research is not found within the tumor itself, but in a seemingly distant location: our gut. Today, we know that the trillions of microorganisms that inhabit the gastrointestinal tract, collectively known as the gut microbiota, can play a decisive role in how patients respond to certain treatments, including immunotherapy.

An increasing number of studies suggest that specific intestinal bacterial species can enhance the effectiveness of treatments such as immune checkpoint inhibitors (ICIs) and even advanced cellular therapies such as CAR-T.

 

An invisible ecosystem with enormous influence

The human body harbors approximately 40 trillion microorganisms, including bacteria, fungi, archaea, and viruses. More than 97% of them reside in the large intestine. Far from being passive passengers, these microorganisms actively participate in metabolic, immunological, and neurological processes that are essential for human health.

In fact, it is estimated that between 60% and 70% of peripheral immune cells—those continuously circulating through the bloodstream or patrolling tissues—are associated with the gut. This is why many researchers consider the intestine to be the body’s largest peripheral immune organ.

The gut microbiota produces bioactive molecules capable of communicating with the immune system. These include short-chain fatty acids, tryptophan-derived metabolites, and various secondary bile acids. Such compounds can influence the activity of key immune cells, including T lymphocytes, dendritic cells, macrophages, and natural killer (NK) cells.

 

Why do some patients respond to immunotherapy while others do not?

Immunotherapy has revolutionized cancer treatment over the past decade. Drugs targeting PD-1, PD-L1, and CTLA-4 have achieved durable responses in patients with melanoma, lung cancer, renal cell carcinoma, and other solid tumors.

However, a significant challenge remains: only a fraction of patients derive substantial benefit. Even among the cancer types most responsive to immunotherapy, only about 20–40% of patients experience favorable outcomes.

For many years, researchers attempted to explain this variability solely through tumor-related factors, such as tumor mutational burden (TMB) or PD-L1 expression. Today, the gut microbiota is recognized as an additional factor capable of profoundly influencing therapeutic efficacy.

One of the most surprising discoveries came in 2015, when researchers demonstrated that certain intestinal bacteria could improve the effectiveness of immunotherapy in experimental models.

 

Among the most extensively studied species are:

• Bifidobacterium longum

• Akkermansia muciniphila

• Bacteroides fragilis

• Faecalibacterium prausnitzii

• Various members of the Ruminococcaceae and Lachnospiraceae families

 

Multiple clinical studies have shown that patients who respond better to PD-1 inhibitors often exhibit a higher abundance of these bacterial species compared with non-responders.

For example, studies in melanoma demonstrated that patients with elevated levels of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium were more likely to respond to anti-PD-1 therapy. Similarly, in lung cancer and renal cell carcinoma, the presence of Akkermansia muciniphila has been associated with improved clinical outcomes.

 

How do gut bacteria enhance immunotherapy?

The answer involves multiple biological mechanisms.

Intestinal bacteria can stimulate the maturation of dendritic cells, which are among the most important antigen-presenting cells of the immune system. These cells are essential for activating cytotoxic T lymphocytes capable of recognizing and destroying tumor cells.

In addition, some microorganisms promote the production of pro-inflammatory cytokines such as IL-12 and interferon-gamma (IFN-γ), molecules that are critical for generating robust anti-tumor immune responses. They can also promote macrophage polarization toward the M1 phenotype, which is associated with anti-tumor activity, and increase the infiltration of CD8+ T cells into the tumor microenvironment.

In other words, certain bacteria help “train” the immune system to better recognize cancer and respond more effectively when immunotherapy is administered.

The influence of the microbiota depends not only on the bacteria themselves but also on the molecules they produce.

Short-chain fatty acids, particularly butyrate and propionate, play important roles in immune regulation. These compounds can influence T-cell differentiation and promote more effective anti-cancer immune responses.

Another particularly interesting metabolite is inosine, produced by bacteria such as Akkermansia muciniphila and Bifidobacterium longum. Recent studies suggest that inosine can increase tumor immunogenicity and enhance T-cell activity through pathways involving IL-12 and IFN-γ.

Likewise, tryptophan-derived metabolites can modulate immune cell activity through signaling pathways involving the aryl hydrocarbon receptor (AhR), which plays important roles in inflammation, cellular differentiation, and anti-tumor immunity.

 

When antibiotics become a problem

One of the most consistent findings in the scientific literature is the association between recent antibiotic use and reduced immunotherapy efficacy.

Several clinical studies have observed that patients who receive antibiotics before or during immunotherapy tend to have lower response rates and reduced survival. The most likely explanation is that antibiotics alter the composition of the gut microbiome and eliminate beneficial bacterial species required for optimal immune responses.

This does not mean that antibiotics should be avoided when medically necessary, but it highlights the importance of using them judiciously and considering their potential effects on the intestinal ecosystem.

 

Fecal microbiota transplantation: a new frontier

Perhaps one of the most fascinating developments in this field is fecal microbiota transplantation (FMT).

This technique involves transferring intestinal microbiota from a healthy donor (or from a patient who responded favorably to immunotherapy) to a patient who has not responded to treatment.

Clinical trials in metastatic melanoma have shown that some patients who were resistant to PD-1 inhibitors regained sensitivity to therapy after receiving microbiota from responders.

Although this strategy remains in the early stages of development, it provides compelling evidence that modifying the microbiome can alter cancer treatment outcomes.

 

Beyond PD-1 inhibitors: effects on CAR-T and other therapies

The influence of the microbiota is not limited to immune checkpoint inhibitors.

Recent studies indicate that gut bacterial composition can also affect the efficacy of advanced cellular therapies such as CAR-T. Certain bacterial species have been associated with improved CAR-T cell expansion, better survival outcomes, and a lower risk of severe toxicities such as cytokine release syndrome.

Furthermore, microbial metabolites can enhance the cytotoxic activity of T lymphocytes and improve the immune system’s ability to eliminate malignant cells.

Figure 1. Gut microbiota supports anti-tumor immunity by enhancing immune activation, tumor infiltration, and immunotherapy response.

 

Can diet improve cancer treatment response?

Growing evidence suggests that dietary habits can modify the microbiome in clinically meaningful ways.

High-fiber diets promote the growth of bacteria that produce butyrate and other beneficial metabolites. They have also been associated with increased abundance of Akkermansia muciniphila and members of the Ruminococcaceae family, microorganisms linked to improved immunotherapy responses.

Conversely, dietary patterns low in fiber and rich in ultra-processed foods may contribute to chronic inflammation and reduced microbial diversity.

Although there is not yet a universal “anti-cancer diet,” research increasingly points toward personalized nutritional interventions as a complementary strategy to optimize cancer treatment outcomes.

 

Toward truly personalized medicine

In the near future, physicians may evaluate not only tumor mutations and immune biomarkers before initiating treatment, but also the composition of each patient’s gut microbiome.

The integration of sequencing technologies, multi-omics analyses, artificial intelligence, and metabolomic studies may allow researchers to identify microbial profiles associated with a greater likelihood of therapeutic success.

As our understanding of these interactions continues to grow, strategies such as precision probiotics, microbiota transplantation, microbial metabolite supplementation, and personalized dietary recommendations may become routine components of cancer care.

 

This article is intended solely for educational and informational purposes. It is not intended to provide medical advice, diagnosis, or treatment recommendations. Readers should consult qualified healthcare professionals regarding any medical concerns or decisions related to their health.

 

Main reference:

Lei, W., Zhou, K., Lei, Y., Li, Q., & Zhu, H. (2025). Gut microbiota shapes cancer immunotherapy responses. NPJ biofilms and microbiomes, 11(1), 143. https://doi.org/10.1038/s41522-025-00786-8 

 

Other reference:

Jiang, S. S., Kang, Z. R., Chen, Y. X., & Fang, J. Y. (2025). The gut microbiome modulate response to immunotherapy in cancer. Science China. Life sciences, 68(2), 381–396. https://doi.org/10.1007/s11427-023-2634-7 

Xie, Y., & Liu, F. (2024). The role of the gut microbiota in tumor, immunity, and immunotherapy. Frontiers in immunology, 15, 1410928. https://doi.org/10.3389/fimmu.2024.1410928