Metabolomic and transcriptomic profiling of HNSCC identifies AMIGO2 as a therapeutic target modulating tumor microenvironment

NPJ Precis Oncol. 2025 Nov 18;9(1):358. doi: 10.1038/s41698-025-01132-z.

Gan Liu ^# ¹ ², Xinfeng Yao ^# ³, Yuchen Hou ^# ⁴, Wentao Deng ³, Liyu Zhang ¹, Shutong Li ⁵, Panpan Huang ⁶, Wenjiao Chang ², Haiyan Huang ¹, Lan Shi ², Qianqian Zhou ⁷, Yanqing Wang ¹, Jia Chen ¹, Wenchao Gu ⁸, Xiaoling Ma ², Yu Zhou ⁹, Honghong Liu ¹⁰, Shanshan Zhang ¹¹, Zongcheng Yang ¹²

Affiliations

1 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
2 Department of Clinical Laboratory, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
3 Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
4 Department of Hepatobiliary Surgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
5 Section of Infection and Immunity, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, CA, USA.
6 Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
7 Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
8 Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
9 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
10 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
11 Department of Medical Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
12 Department of Stomatology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China. [email protected].
# Contributed equally.

PMID: 41254143 DOI: 10.1038/s41698-025-01132-z

Abstract

Extensive studies have demonstrated the relationship between metabolic reprogramming and the tumor microenvironment. Here, we characterized the head and neck squamous cell carcinoma (HNSCC) evolutionary landscape using spatial metabolomics/transcriptomics, single-cell transcriptomics, and bulk multi-omics. Metabolic heterogeneity during HNSCC malignant transformation was identified, with significant enrichment in the purine metabolism. Integrating single-cell and bulk data, we developed a robust ligand-receptor-based signature (LRS) linked to NT5E, a key upstream regulator of purine metabolism, which served as an independent prognostic indicator. The low LRS subtype was associated with a high proportion of immune cell infiltration and improved response to immunotherapy. Notably, in vitro and in vivo experiments demonstrated that AMIGO2, a core molecule within the LRS, regulates tumor-associated purine metabolism, and that its downregulation suppresses tumor cell invasion and migration, inhibits myofibroblast differentiation, and promotes immune effector cell infiltration. Moreover, combining AMIGO2 targeting with anti-PD-1 therapy yielded superior efficacy. Consistent validation was also obtained in a clinical cohort of HNSCC and premalignancy patients.

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