Why Some Cancer Patients Don't Respond to Immunotherapy—And What Bacteria Have to Do With It

Cleveland Clinic researchers have discovered that bacteria living inside cancerous tumors may explain why immunotherapy works brilliantly for some cancer patients but fails others entirely. Two groundbreaking studies published in Nature Cancer found that elevated bacterial levels in head and neck tumors suppress the immune response, creating resistance to immunotherapy treatments.

How Do Bacteria Interfere With Cancer Treatment?

The research team, led by Dr. Timothy Chan and colleagues, analyzed genetic data from patient tumor samples and found something unexpected: higher bacterial levels—regardless of the specific bacterial strains—consistently weakened immune responses. When they tested this theory in laboratory models, the results were striking. Antibiotics reduced tumor size and improved immune response, while adding bacteria made tumors resistant to immunotherapy.

"These studies shift the focus of immunotherapy resistance research beyond tumor genetics to unexpected factors like the tumor microbiome," said Timothy Chan, M.D., Ph.D., chair of Cleveland Clinic's Department of Cancer Sciences.

What Happens When Bacteria Invade Tumors?

The mechanism behind this bacterial interference involves a complex immune system response. When bacteria accumulate in tumors, they attract neutrophils—white blood cells designed to fight infections. While neutrophils are essential for battling bacterial infections, their presence in cancer creates an unintended consequence:

• Immune Suppression: Neutrophils suppress the very immune system activity that immunotherapy relies on to attack cancer cells
• Treatment Resistance: Patients with high tumor bacteria levels showed poorer outcomes when receiving immunotherapy compared to standard chemoradiotherapy
• Weakened Response: The bacterial presence essentially hijacks the immune system, redirecting it away from fighting cancer

What Does This Mean for Cancer Patients?

The findings were validated through analysis of the Javelin HN100 Phase III clinical trial, which tested whether adding anti-PD-L1 immunotherapy to standard chemoradiotherapy improved outcomes for patients with head and neck squamous cell carcinoma. The data confirmed that patients with high tumor bacteria levels had significantly worse outcomes with immunotherapy.

"Immunotherapy is a promising treatment option for patients with head and neck cancer, but the majority unfortunately do not respond," explained Dr. Natalie Silver, director of Head and Neck Cancer Research at Cleveland Clinic. This research could help identify which patients are most likely to benefit from immunotherapy, potentially avoiding unnecessary treatments and side effects.

Building on these discoveries, Dr. Silver has launched a clinical trial funded by the American Cancer Society to test whether antibiotics can lower tumor bacteria levels and boost immunotherapy response in head and neck cancer patients. Meanwhile, other researchers are investigating why bacteria are attracted to tumors in the first place and how to modify the tumor environment to improve treatment effectiveness.

"By uncovering the tumor microbiome's role in immunotherapy resistance, these studies mark a significant step forward in understanding the complex interactions between cancer and the immune system," said Dr. Daniel McGrail, assistant staff in the Center for Immunotherapy & Precision Immuno-Oncology. This research opens the door to new strategies for patient selection and targeted antibiotic therapies, potentially transforming outcomes for cancer patients who don't currently benefit from immunotherapy.