In cancer research, failure can lead to an important discovery. That’s what happened when an international multicenter trial led by MSK radiation oncologist and early drug development specialist Nancy Lee, MD, tried combining radiation and chemotherapy with an immunotherapy drug to treat cancers of the head and neck. The method had been effective in people with melanoma and lung cancer.
Disappointingly, the approach did not work for most head and neck cancer patients.
And that made Dr. Lee and her colleagues determined to understand why. They discovered that the bacteria inside tumors can affect the response to immunotherapy. If a tumor has a high level of bacteria, it attracts immune cells called myeloid cells. But these myeloid cells, instead of boosting the immune response, tamp it down — the opposite of the desired effect.
Their discovery suggests that altering the bacteria in tumors — perhaps with something as simple as antibiotics — could make immunotherapy work much better.
“This could be a completely new tactic for modifying the tumor and its microenvironment to improve outcomes,” says radiation oncologist Nadeem Riaz, MD, MSc, first author on the paper. “It would be straightforward to add antibiotics to treatment, which are well-tested and safe, to overcome resistance in certain patients.”
The findings were published in Nature Cancer on January 2, 2026.
Apart from the possible effectiveness of antibiotic treatment, the researchers now have a way to gauge which patients are likely to respond better to immunotherapy: those with lots of T cells and lower levels of bacteria and myeloid cells at the tumor site.
Clinical Trial Adds Avelumab to Chemoradiotherapy for Head and Neck Cancers
Dr. Lee led a phase 3 international multicenter clinical trial called JAVELIN Head and Neck 100. The trial was investigating whether the checkpoint inhibitor drug avelumab (Bavencio®) could be effective when added to the standard treatment of chemotherapy and radiation (chemoradiotherapy) for patients with squamous cell carcinoma of the head and neck.
Dr. Riaz and Dr. Lee, along with Timothy Chan, MD, PhD, and colleagues at the Cleveland Clinic, looked closely at differences between those tumors in the study that responded to the treatment and those that didn’t. They analyzed the genetic makeup of the tumors and their microenvironment cells, including immune cells that had been drawn to the area.
The clinical trial for squamous cell carcinoma found:
- In people who fared well, the tumors and microenvironment were filled with immune T cells, which attacked the cancer.
- People who responded poorly to treatment had high levels of myeloid cells that had flocked to the tumor microenvironment.
- Specifically, this patient group had high levels of a type of myeloid cell called neutrophils. Neutrophils are part of the innate immune system and the first responders to signs of trouble. They swoop into the area and begin releasing toxic chemicals while also gobbling up pathogens. But neutrophils can impair the immune response by suppressing the immune T cells that attack cancer cells.
“We’ve known for quite some time that neutrophils are associated with a bad prognosis in cancer, but it’s been very hard to figure out why some tumors seem to attract them, while other tumors attract T cells,” Dr. Riaz says. “Now we have solid proof that bacteria in the tumors is drawing in myeloid cells, especially neutrophils, and shaping the microenvironment to resist immunotherapy.”
“This research finally gives us the answer on why we cannot deliver immunotherapy at the same time as radiation. This has tremendous implication on how we design future trials,” Dr. Lee says.
Clearing the Bacteria Inside Tumors
Dr. Riaz says the next step will be to see whether it’s possible to alter bacteria in the tumor and change the microenvironment, to make therapy work better.
“In the last decade, there was a lot of interest in the gut bacteria. People jumped in and tried to reprogram it, only to find out that it’s much harder to do than they expected,” Dr. Riaz says. “The mouth has very diverse bacteria. So we first want to see if it’s even possible to clear it from these head and neck tumors in a way that affects the microenvironment the way we want.”
To test this, the researchers plan to open a clinical trial in 2026 in which they will look at tumors in people with head and neck cancer who are scheduled for surgery. Two weeks before surgery, they will take a biopsy to measure bacteria in the tumor and the microenvironment. Patients with high bacterial levels will get a course of antibiotics leading up to the surgery. After the surgery, the researchers will study the removed tumor to see if the bacteria have been wiped out — and also if the tumor microenvironment has changed.
MSK’s History of Treating Head and Neck Cancer
Dr. Lee, MSK’s Service Chief of Head & Neck Radiation Oncology, has played a pioneering role in developing and testing treatment approaches for head and neck cancers. This includes using a sharply reduced radiation dose in the treatment of HPV-related cancers to prevent side effects, as well as showing that adding the checkpoint inhibitor drug pembrolizumab (Keytruda®) to standard treatments before and after surgery for head and neck cancers significantly reduced risk of disease progression, recurrence, and death. This has gained FDA approval. She is the principal investigator for numerous other national and international clinical trials and has authored numerous articles focusing on head and neck cancers with the goal of defining appropriate treatment for people with these diseases.
Dr. Riaz is Associate Director, Genomics Operations, Immunogenomics and Precision Oncology Platform. He researches how the genetics of a tumor influence its response to traditional therapies and to newer treatments like immunotherapies. Dr. Riaz is working to make tumor analyses available to more patients so their treatment can more precisely match their type of cancer.
“What’s unique about MSK is we have the entire research infrastructure to make new discoveries and learn from clinical trial results that are negative. That’s how we found the bacterial connection,” Dr. Riaz says. “It’s not something that would have happened in industry — after the combination treatment failed, they would have stopped looking at it. But we have the resources here to find answers that can lead to breakthroughs.”
Additional Authors, Funding, and Disclosures
Additional MSK authors on the study are Yingjie Zhu, Ardijana Novaj, and Ana Gradissimo.
Funding for this study includes NIH/NCI Cancer Center Support Grant P30 CA008748. This trial was sponsored by Pfizer and was previously conducted under an alliance between Merck (CrossRef Funder ID: 10.13039/100009945) and Pfizer.
Additional funding sources are listed in the paper.
Dr. Riaz acknowledges research support from Pfizer, REPARE Therapeutics, Invitae, and Bristol-Meyers.
Key Takeaways
- A clinical trial using radiation and chemotherapy combined with immunotherapy for head and neck cancer had disappointing results.
- MSK researchers found that people whose tumors had high levels of bacteria did worse.
- Tumor bacteria attract large numbers of immune myeloid cells, which interfere with the immunotherapy response.
- Removing the bacteria from the tumors might prevent myeloid cells from coming to the tumor, making checkpoint blockade drugs work better.
