Two studies published simultaneously in Nature Cancer have identified elevated levels of bacteria within tumors as a major factor contributing to immune suppression and resistance to immunotherapy in patients with head and neck squamous cell carcinoma. The findings offer important insights into why only a subset of patients achieve durable benefit from immunotherapy and suggest new approaches to improving clinical outcomes.
Immunotherapy has become an important treatment option for head and neck cancer, but long-term responses remain limited to a minority of patients. The new research indicates that the tumor microbiome, defined as the total bacterial content within the tumor microenvironment, plays a decisive role in determining whether immunotherapy is effective.
In the first study, researchers analyzed genetic and microbiome data from tumor samples of patients with head and neck cancer. Tumors with a higher overall bacterial burden consistently showed reduced immune activity, regardless of the specific bacterial species present. This suggests that immune suppression is driven by the total quantity of bacteria rather than by individual pathogenic organisms.
These findings were supported by preclinical models. Reducing intratumoral bacterial levels using antibiotics led to slower tumor growth and improved antitumor immune responses, while increasing bacterial levels promoted resistance to immunotherapy. Analyses of samples from clinical trials further reinforced this association, demonstrating that patients with higher tumor bacterial loads experienced poorer responses to treatment.
The second study examined data from a large Phase III clinical trial evaluating the addition of PD-L1–directed immunotherapy to standard chemoradiotherapy in patients with head and neck squamous cell carcinoma. Although overall trial results were mixed, a clear pattern emerged on stratified analysis. Patients whose tumors contained high bacterial levels had worse outcomes when immunotherapy was added, compared with those treated with chemoradiotherapy alone.
Mechanistic investigations across both studies revealed that high intratumoral bacterial burden was associated with increased recruitment of neutrophils. While neutrophils are essential for controlling bacterial infections, their accumulation within tumors can suppress the activity of cytotoxic T cells that are critical for immunotherapy efficacy. As a result, immune responses are redirected away from tumor eradication, allowing cancer cells to persist despite treatment.
These findings highlight the complex interactions between cancer, the immune system and microorganisms residing within tumors. They also help explain why some patients with otherwise favorable clinical features derive little or no benefit from immunotherapy.
The research provides a rationale for incorporating tumor microbiome profiling into treatment decision-making and for developing strategies aimed at modulating intratumoral bacterial levels. Approaches such as targeted antibiotic therapy or other microbiome-modifying interventions may help restore immune responsiveness and enhance the effectiveness of immunotherapy. A clinical trial is already underway to evaluate whether reducing the tumor microbiome can improve immunotherapy responses in patients with head and neck squamous cell carcinoma.
Ongoing studies are investigating why certain tumors harbor higher bacterial loads and whether intratumoral bacteria contribute directly to cancer development, including through mechanisms such as DNA damage and mutagenesis. These findings represent an important step toward more personalized treatment strategies in head and neck cancer and may help spare patients from ineffective therapies while improving outcomes for those with limited options. As this field evolves, targeting tumor-associated bacteria may emerge as a novel therapeutic approach, with the potential to enhance the durability and effectiveness of immunotherapy.
Reference
- Riaz N, Alban TJ, Haddad RI, Saul M, Makarov V, Zhu Y, 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;1–18.
- Silver NL, Dai J, Kerr TD, Altemus J, Garg R, Simmons H, et al. Intratumoral bacteria are immunosuppressive and promote immunotherapy resistance in head and neck squamous cell carcinoma. Nat Cancer. 2026 Jan 2;1–18.