Two newly published studies from Cleveland Clinic researchers have found that elevated bacteria levels in head and neck cancer tumours weaken the immune response, paving the way for new therapeutic strategies.
Bacteria inside cancerous tumours may be key to understanding why immunotherapy works for some patients but not others.
Two new studies, published simultaneously in Nature Cancer, reveal that elevated levels of bacteria in the tumour microenvironment suppress immune response, driving resistance to immunotherapy in patients with head and neck squamous cell carcinoma.
“These studies shift the focus of immunotherapy resistance research beyond tumour genetics to unexpected factors like the tumour microbiome,” said Timothy Chan MD PhD (pictured above), Chair of Cleveland Clinic’s Department of Cancer Sciences and lead author of one of the papers. “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.”
The research team, led by Dr Chan, Daniel McGrail PhD, assistant staff in the Center for Immunotherapy and Precision Immuno-Oncology, and Natalie Silver MD MS, Director of Head and Neck Cancer Research, validated the findings through patient samples, preclinical models and clinical trial data.
In the first paper, Dr McGrail analysed genetic data from patient tumour samples, revealing that higher bacterial levels – not specific strains – weaken immune response. Dr. Silver confirmed these findings in preclinical models: antibiotics reduced tumour size and improved immune response, while adding bacteria made tumours resistant to immunotherapy. The team also worked with Renata Ferrarotto MD, from the University of Texas MD Anderson Cancer Center to study the relationship between bacteria and treatment responses in head and neck cancer patient clinical trial samples.
“Immunotherapy is a promising treatment option for patients with head and neck cancer, but unfortunately the majority do not respond,” Dr Silver said. “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. Ultimately, we aim to develop targeted interventions that restore the effectiveness of immunotherapy in for patients who do not initially respond.”
In the second paper, Dr Chan led a data analysis of the Javelin HN100 Phase III clinical trial, which tested whether adding anti-PDL1 immunotherapy to standard chemoradiotherapy improved outcomes for patients with head and neck squamous cell carcinoma. The analysis confirmed that patients with high tumour bacteria levels had poorer outcomes with immunotherapy compared to standard chemoradiotherapy. The trial included collaborators from Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute.
Together, the two studies showed that elevated bacteria levels in tumours attract neutrophils, white blood cells that fight infection. While neutrophils are essential for combating bacterial infections, in cancer they can suppress the immune system needed for immunotherapy to work effectively. These findings lay the foundation for future research on why bacteria are attracted to tumours and how to modify them to improve treatment.
Building on these discoveries, Dr Silver has launched a clinical trial funded by the American Cancer Society and VeloSano, a Cleveland Clinic fund-raising movement to beat cancer, to test whether antibiotics can lower tumour microbiome levels and boost immunotherapy response in patients with head and neck squamous cell carcinoma. Meanwhile, Dr McGrail is studying how bacteria influence cancer development and why some tumours harbour more bacteria, aiming to develop new therapeutic strategies, and Dr Chan is exploring how bacteria may induce DNA mutations in tumours.
“By uncovering the tumour 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 McGrail. “This research broadens our perspective on cancer treatment and paves the way for developing personalised therapies to improve outcomes for patients.”
- Riaz N, Alban TJ, Haddad RI, et al. Tumor ecosystem and microbiome features associated with efficacy and resistance to avelumab plus chemoradiotherapy in head and neck cancer. Nat Cancer. 2026 Jan 2. doi:10.1038/s43018-025-01068-0. Online ahead of print.
- Silver NL, Dai J, Kerr TD, et al. Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma. Nat Cancer. 2026 Jan 2. doi:10.1038/s43018-025-01067-1. Online ahead of print.