Stratifying the immune landscape of tongue cancer

Immune environments in most tongue cancer tumors help identify cases for effective treatment, report researchers from Institute of Science Tokyo. By profiling immune cell presence and activity in tumor samples from 87 patients, they identified five immunotypes, with most patients categorized in these immunotypes featuring low immune engagement. These findings explain why immune checkpoint inhibitors prove inefficacious in tongue cancer and suggest that immune-based classification could better guide personalized treatment strategies.

Immunotherapies are undoubtedly transforming the landscape of cancer treatment worldwide. By harnessing the body’s immune system to fight disease, they can achieve outcomes in advanced cancers that are impossible with conventional methods. However, these revolutionary therapies don’t work equally well for all patients and cancer types.

For example, despite the promise of immune checkpoint inhibitors (ICIs)—drugs that cancel inhibitory signals to effector T cells—their effectiveness against head and neck squamous cell carcinoma (HNSCC) has been disappointing. While these therapies yield impressive results in melanoma and lung cancer, only about 10% of patients with HNSCC experience durable responses. Tongue squamous cell carcinoma (TSCC), the most common type of oral cancer, is particularly challenging due to the tongue’s continuous exposure to environmental stimuli and immunotolerant status.

Shedding light on this issue, a research team led by Professor Miyuki Azuma from Institute of Science Tokyo, Japan, expanded a TSCC cohort of comprehensive immune profiling analyses, published in the previous paper, in Volume 143 of Oral Oncology in 2023, and conducted classification of TSCC immune profiling, published online in Volume 74 of Cancer Immunology, Immunotherapy on March 01, 2025.

The researchers employed advanced multiplex immunofluorescence and tissue imaging techniques to analyze the presence and distribution of various immune cells within tumors. They also conducted spatial analysis to quantify distances between tumor cells and cytotoxic T lymphocytes, an important subtype of immune cells that can kill cancer cells.

Based on the gathered data and statistical analyses, the team identified five distinct immunotypes. Immunoactive type I profiles would likely respond well to current immunotherapies. In contrast, immunosuppressed type III showed active suppression of immune responses, and immunoisolating type IV featured immune cells that were unable to engage with cancer cells. Finally, immunodesert type V was marked by an almost complete lack of immune cell infiltration.

“We found that the immunoactive type, which would be sensitive to ICI monotherapy, was rare, and most TSCC cases exhibited immune-regulated immunotypes,” explains Azuma. Specifically, about 70% of untreated TSCC tumors fell into types III–V, explaining why current immunotherapies targeting programmed cell death protein often fail.

Additionally, the researchers found that tumor-node-metastasis staging, a traditional cancer classification system, cannot accurately predict a tumor’s immune profile. This finding highlights the need for immune-based assessments to guide treatment decisions. The team believes that immunotype classification system could help clinicians identify patients who can benefit from immunotherapy alone versus those who need combination approaches. For example, patients with type I tumors might respond well to standard ICIs, while those with types III–V might require additional interventions to overcome immunosuppression. “We expect the results of this study to promote personalized medicine in tongue cancer, enabling the selection of optimal treatments for more patients and contributing to improved treatment outcomes,” concludes Azuma.

Overall, this study represents an important step toward precision oncology for patients with TSCC, potentially improving treatment responses and guiding them toward successful immune landscape-based therapies.

Authors:

Yuya Su^1,2,3, Ryo Ouchi^3,4, Pissacha Daroonpan^3,5, Miwako Hamagaki⁶, Tohru Ikeda⁷, Noji Rika¹, Naoto Nishii¹, Fumihiko Tsushima¹, Yoshihito Kano⁸, Takahiro Asakage⁹, Makoto Noguchi⁴, Hiroyuki Harada¹, and Miyuki Azuma^1,2,3*

Title:

Stratification of the immunotypes of tongue squamous cell carcinoma to improve prognosis and the response to immune checkpoint inhibitors

Journal:

Cancer Immunology, Immunotherapy

DOI:

10.1007/s00262-025-03982-9

Affiliations:

¹Department of Oral and Maxillofacial Surgical Oncology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Japan
²Oral Science Center, Institute of Science Tokyo, Japan
³Department of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan
⁴Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, Japan
⁵Department of Oral Diagnosis, Naresuan University, Thailand
⁶Division of Surgical Pathology, Institute of Science Tokyo Hospital, Japan
⁷Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Japan
⁸Department of Medical Oncology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Japan
⁹Department of Head and Neck Surgery, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Japan

• SU Yu Ya | Science Tokyo Research Information DB
• HARADA Hiroyuki | Science Tokyo Research Information DB
• Institute of Integrated Research

• Oral Science Center, Institute of Science Tokyo
• Graduate School of Medical and Dental Sciences

• School of Pharmacy and Pharmaceutical Sciences, University of Toyama