From Resistance to Response: The Microbiome’s Role in Optimizing Cancer Therapy

Resistance remains one of the most significant barriers to optimal treatment outcomes and overall survival for patients across cancer types. Although genetic mutations play a key role in poor therapeutic responses, the gut microbiome may also interfere with critical therapies in the cancer treatment landscape. Studies show that disruptions in gut microbiota are associated with resistance and less favorable responses to immunotherapies.

Drawing of the gut microbiome | Image Credit: © ArtemisDiana - stock.adobe.com

Deeper knowledge of the integral relationship between the gut and cancer therapy is critical for maintaining the integrity and efficacy of agents that have revolutionized cancer treatment over the past few decades. At the 2025 ASCO Annual Meeting, experts discussed the complexity of the gut microbiota and emerging research highlighting its role in modulating treatment response and resistance mechanisms. These insights highlight the importance of incorporating microbiome-focused strategies into cancer care to enhance therapeutic efficacy and support long-term disease control.¹

How the Gut Microbiome Impacts Therapy Responses

The role of the gut across disease states is a growing area of research, and emerging data show that gut bacteria are active participants in immune system modulation. Research revealed that certain gut bacteria can enhance or suppress immune responses to cancer treatments, particularly immunotherapy. Gut bacteria produce metabolites that influence drug metabolism and affect immune cell function, potentially enhancing or inhibiting treatment effectiveness.¹

Bacterial composition—beyond interfering with immunotherapy response—can also be used as a predictive tool for determining therapy outcomes. In fact, some bacteria species are associated with better responses, whereas others can reduce survival rates. Identifying gut microbiota species and their role as therapeutic enhancers or inhibitors is a critical step in creating a comprehensive guide to personalized cancer treatment.¹

Antibiotics

Antibiotics are crucial drugs for treating infections; however, they do have a detrimental effect on the gut microbiome. Antibiotics significantly reduce microbiome diversity and can suppress immune system effectiveness, which is crucial for the success of immunotherapies. Studies show that antibiotic use in patients with cancer leads to lower overall survival rates and reduced responses to immunotherapy, namely, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and hematopoietic stem cell transplantation. Antibiotic use also increases the risk of death (hazard ratio of 1.7 across studies).¹

Antibiotic exposure impairs multiple immune system functions that are crucial for the success of immunotherapies. Immunosurveillance is a natural function of the immune system that monitors and eliminates nascent tumors before they progress to overt cancer. Antibiotic exposure impairs immunosurveillance, thereby allowing cancer cells to proliferate and reducing overall survival. Antibiotics also increase T-cell exhaustion, which is a widely common complication that interferes with optimal therapeutic responses.¹

The gut microbiome is a complex ecosystem composed of diverse microbial species that play a crucial role in stimulating immune responses. Antibiotic exposure can disrupt this balance by eliminating bacteria with important immunogenic properties.¹

Practical recommendations for antibiotic use include avoiding unnecessary antibiotic prescriptions and using the shortest effective course whenever treatment is necessary. It's important to consider the patient's specific cancer treatment context, as certain therapies may increase susceptibility to infections or alter the microbiome. Additionally, monitoring microbiome changes during antibiotic treatment can help inform future therapeutic decisions and support better outcomes.¹

"Pharmacovigilance in the use of antibiotics should be approached judiciously, such as narrowing the antibiotic spectrum, minimizing polypharmacy, limiting conservative prescribing tendencies, and reducing the duration of therapy," explained Laurence Zitvogel, MD, PhD, from the Institut Gustave Roussy Strategies in Montreal.¹

Gut Dysbiosis

Gut dysbiosis refers to an imbalance in the gut microbiome characterized by reduced microbiome diversity, enrichment of harmful bacteria, and the depletion of beneficial bacteria. It is associated with reduced response to immunotherapy and can be a risk factor for cancer treatment resistance as well as a predictive tool to determine immunotherapy response. Approximately 20% of healthy individuals have some degree of dysbiosis, whereas patients with cancer experience higher rates of about 50% to 60%.¹

"We learned that dysbiosis is a key biomarker of response and resistance to immunotherapy,” said Arielle Elkrief, MD, from the University of Montreal. “As a result, multiple microbiocent interventions and clinical trials are being developed with the goal of transforming an unfavorable microbiome associated with resistance to immunotherapy to that of a favorable microbiome associated with a robust immune response."¹

Gut dysbiosis severity can vary, which does impact treatment approaches. For cases of mild dysbiosis, it is recommended to stop inappropriate medications and make nutritional adjustments that increase fiber intake. Moderate dysbiosis can be treated in many ways, including prebiotics, live bacterial products, and, in some cases, fecal microbiota transplantation (FMT). FMT is the preferred approach for treating severe cases of gut dysbiosis.¹

"We might envision treating mild dysbiosis by discontinuing inappropriate medications and addressing nutritional imbalances,” said Zitvogel. “For moderate dysbiosis, targeting sites of inflammation may be beneficial, along with the use of prebiotics and potentially live biotherapeutics. In cases of severe dysbiosis, even interventions such as fecal microbiota transplantation may prove valuable."¹

Modulating the Gut Microbiome

There are multiple approaches to modulating the gut microbiome to prevent dysbiosis and treatment resistance. These include FMT, dietary interventions, use of prebiotics, and use of probiotics. However, the success of these interventions is determined by a patient’s gut microbiome composition.¹

The goal of FMT is to replace the patient's dysbiotic microbiome with a healthy microbiome to restore beneficial bacterial populations. It is administered as an odorless, tasteless oral capsule that contains approximately 200 grams of healthy donor stool. Patients often receive a bowel preparation 24 hours before transplant to clear the native microbiome.¹

FMT shows promising results in cancer immunotherapy across multiple studies. In the phase 2 TACITO trial (NCT04758507), 66.7% of patients with renal cell carcinoma achieved progression-free survival 1 year following FMT. FMT demonstrates favorable efficacy in other cancers as well. The FMT-LUMINATE study (NCT04951583), assessing FMT in patients with lung cancer, met its primary end point with an 80% overall response rate.^1-3

However, there are some barriers to FMT, including regulatory hurdles, cost, donor availability, and the potential risk of transmitting infections.¹

Dietary interventions are positively correlated with improved microbiome integrity and may play an important role in supporting cancer treatment outcomes. High-fiber diets and the Mediterranean diet have shown potential benefits in modulating the gut microbiome, and fiber intake, in particular, has been linked to improved treatment responses.¹

Supplementation with probiotics or prebiotics offers an affordable and accessible option for many patients; however, it's important to note that probiotics may sometimes reduce microbial diversity rather than resolve dysbiosis. In contrast, prebiotics—substances that beneficially shift the microbiome composition, often through specific nutritional supplements—may contribute to a healthier gut environment and potentially improve the tumor microenvironment.¹

Personalized approaches are increasingly recognized as essential to advancing cancer care, and consideration of the gut microbiome inherently supports this shift. By integrating microbiome insights into clinical decision-making, clinicians can personalize care and enhance the potential for improved treatment responses and overall outcomes. As research continues to uncover the complex interactions between the microbiome and cancer therapies, leveraging this knowledge will be key to optimizing patient-centered care.

REFERENCES

1. McQuade J, Zitvogel L, Elkrief A. The microbiome's influence on cancer therapy: insights and innovations. 2025 ASCO Annual Meeting. May 30, 2025, to June 3, 2025. Chicago, IL.

2. Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO). Updated March 11, 2025. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04758507

3. Fecal microbial transplantation non-small cell lung cancer and melanoma (FMT-LUMINATE). Updated August 7, 2024. Accessed May 31, 2025. https://clinicaltrials.gov/study/NCT04951583