A study led by clinician-scientists and researchers at the National Cancer Centre Singapore (NCCS) has found that the tumor immune microenvironment (TIME) plays a critical role in the progression of nasopharyngeal carcinoma (NPC) commonly known as nose cancer. These insights are paving the way for precision oncology approaches, some of which are currently used in clinical trials at NCCS. The findings are published in Cell Reports Medicine.


NPC is a type of head and neck cancer that originates in the nasopharynx—the passageway behind the nose. It is prevalent in Southeast Asia, Southern China and North Africa and occurs more frequently in men. In Singapore, NPC is the 10th leading cause of cancer death in men and is the third most common cancer in men aged 30 to 49.

Due to the anatomy of the nasopharynx, NPC often spreads insidiously and is typically diagnosed at a locoregionally advanced stage, where cancer has spread within the head but not to distant parts of the body.

There are three subtypes of locoregionally advanced NPC (Stage 3 to 4A):

Ascending: Large primary tumor with limited spread
Descending: Small primary tumor with extensive spread
Ascending/Descending (A/D): Large primary tumor with extensive spread
Despite their biological and clinical differences, all three subtypes are currently treated with the same combination of chemotherapy and radiotherapy, resulting in suboptimal outcomes, with the 3-year recurrence rate of Stage 3 and 4A patients at 20% and 40%, respectively. Outcomes could be improved with individualized treatment strategies, but to do that, the biological mechanisms of the subtypes need to be better understood.


Uncovering key molecular differences in NPC
To uncover molecular distinctions between NPC subtypes, the Precision Radiotherapeutics and Oncology Programme at NCCS, led by internationally renowned NPC clinician-scientist, Associate Professor Melvin Chua (See Annex A), Head and Senior Consultant, Department of Head and Neck and Thoracic, Division of Radiation Oncology, NCCS, performed an in-depth study of NPC tumor biology. The team analyzed samples from 1,076 NPC patients—994 from NCCS and 82 from Jiangxi Cancer Hospital, China at the point of diagnosis.

Using state-of-the-art genomic profiling and spatial transcriptomics, they discovered that each locoregionally advanced subtype of NPC has a distinct TIME that influences disease progression and treatment responsiveness. TIME is the ecosystem that surrounds and supports a tumor. Notably, the Ascending subtype displayed an "immune-low" TIME, suggesting limited efficacy for immunotherapy, while the Descending subtype had an "immune-high" TIME, indicating greater potential responsiveness to immunotherapy.

This is the first large-scale study to show that TIME plays a defining role in NPC progression from early stage to the locoregionally advanced NPC, with direct implications for personalized patient care.


Clinical characteristics and germline variants associated with NPC subtypes (n = 303 [L], 201 [A], 246 [D], and 244 [AD]). Credit: Cell Reports Medicine (2025). DOI: 10.1016/j.xcrm.2025.102143
Implications for treatment and clinical trials
"We mapped the nasopharyngeal tumor immune ecosystem and showed the drastic differences between tumors, which explain why some patients may not respond well to treatment," said senior author Associate Professor Chua. "This validates clinical trials ongoing at the National Cancer Centre Singapore and we look forward to improving treatment response rates and survival outcomes."

These trials include the RIBBON-UM study, that started in 2022, which stratifies patients with Stage 2 to 4 NPC based on their tumor stage and Epstein-Barr virus (EBV) DNA levels. While EBV is common worldwide, it is strongly linked with NPC in Asian populations and associated with worse outcomes when present in higher levels in the blood.

RIBBON-UM is divided into two arms with:

Low-risk patients receiving concurrent chemoradiotherapy with optional adjuvant therapy
High-risk patients receiving induction chemotherapy. Those with persistent EBV DNA levels post-treatment may be enrolled in RIBBON-LA-01, a Phase 2 trial evaluating immunotherapy (tislelizumab) given with metronomic chemotherapy (capecitabine)
RIBBON-LA-01 has recruited 12 patients to date, with a target of 69, and is conducted at NCCS and Tan Tock Seng Hospital.

Redefining NPC staging for better prognostication
In addition to molecular research, Associate Professor Chua led a global consortium that updated the NPC staging system used in clinical care. Published in JAMA Oncology in October 2024, the refined system better distinguishes between locally advanced and metastatic NPC, addressing a critical gap in patient communication and care planning.

Key changes include the reassignment of previous Stage III and IVA into Stages II and III and restricting Stage IV to metastatic disease. This updated framework has been in clinical use since January 2025 and helps clinicians when counseling patients and planning treatment.

Together, these efforts reflect and reinforce NCCS' commitment to advancing translational cancer research that informs and improves patient care.