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 bacteria levels in head and neck tumors suppress the immune system, creating resistance to immunotherapy treatments.

How Do Bacteria Block Cancer Treatment?

The research team, led by Dr. Timothy Chan and colleagues, analyzed patient tumor samples and found something unexpected: higher bacterial levels—not specific bacterial strains—weaken the body's immune response against cancer. When they tested this theory in laboratory models, 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. "By identifying bacteria as a key barrier to treatment, we're opening the door to new strategies for patient selection and targeted antibiotic therapies, potentially improving outcomes for those who don't benefit from immunotherapy."

What Makes This Discovery So Important?

The findings were validated through multiple approaches, including 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. Patients with high tumor bacteria levels had significantly poorer outcomes with immunotherapy compared to standard treatment alone.

The mechanism works like this: elevated bacteria levels attract neutrophils, white blood cells designed to fight infections. While neutrophils are essential for battling bacterial infections, in the cancer environment they actually suppress the immune system that immunotherapy needs to function effectively. The research revealed several key factors about this process:

• Bacterial Load Matters: Higher overall bacterial levels, rather than specific bacterial species, correlate with treatment resistance
• Neutrophil Response: Bacteria attract infection-fighting cells that inadvertently weaken anti-cancer immunity
• Treatment Timing: Patients with high bacterial loads showed poorer responses specifically to immunotherapy combinations
• Therapeutic Potential: Antibiotic treatments successfully reduced tumor bacteria and improved immune response in laboratory models

What Does This Mean for Cancer Patients?

"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. "Our research examines how bacteria influence treatment failure. This can help us identify patients most likely to benefit from immunotherapy, with the goal of avoiding unnecessary risk and exposure."

Building on these discoveries, Dr. Silver has launched a clinical trial funded by the American Cancer Society and VeloSano to test whether antibiotics can lower tumor bacteria levels and boost immunotherapy response in patients with head and neck squamous cell carcinoma. Meanwhile, other team members are studying why some tumors harbor more bacteria and how bacteria might induce deoxyribonucleic acid (DNA) mutations in tumors.

This research represents a significant shift in understanding cancer treatment resistance. Rather than focusing solely on tumor genetics, scientists now recognize the tumor microbiome—the community of bacteria living within cancerous tissue—as a crucial factor in treatment success. The findings could lead to personalized treatment approaches where doctors test tumor bacteria levels before selecting immunotherapy, potentially improving outcomes for the majority of head and neck cancer patients who currently don't respond to these treatments.