SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma
Subtle variations of micronutrients in the tumor microenvironment often coincide with tumor progression and immune disorders. Nevertheless, the underlying mechanisms of how micronutrients, such as metal ions, influence tumor-intrinsic properties and tumor-immune crosstalk remain inadequately characterized. Here, our integrative analysis of multi-center single-cell, spatial transcriptome sequencing, and bulk RNA sequencing (RNA-seq) cohorts reveals that nasopharyngeal carcinoma (NPC)-specific SRY-box transcription factor 4 (SOX4) governs microenvironmental and cellular zinc metabolism through its downstream target, SLC39A14 (ZIP14), a membrane zinc uptake transporter. Mechanistically, NPC cells enhance zinc uptake and activate Wnt/β-catenin signaling to initiate tumor growth, creating a zinc-deficient niche hostile to T cells. Zinc deficiency of tumor-infiltrating CD8<sup>+</sup> T cells impairs LCK phosphorylation and T cell receptor (TCR) signaling, compromising their effector function. Our study elucidates the idea that the SOX4-ZIP14-zinc metabolism axis has a multifactorial effect in NPC, fostering the malignant phenotypes of NPC and suppressing the T cell response through the deprivation of zinc metabolism.
Authors
- Wei Dai (ORCID: https://orcid.org/0000-0003-1650-1590)
- Jiao Huang (ORCID: https://orcid.org/0000-0002-6275-0451)
- Lanqi Gong (ORCID: https://orcid.org/0000-0002-1531-4948)
- Jishi Li
- Baifeng Zhang (ORCID: https://orcid.org/0000-0003-1966-2285)
- Xiaona Fang (ORCID: https://orcid.org/0000-0001-5325-4686)
- Lu Bai (ORCID: https://orcid.org/0000-0003-4882-6672)
- Ching Ngar Wong (ORCID: https://orcid.org/0000-0002-5034-7067)
- Shanshan Li (ORCID: https://orcid.org/0000-0002-4092-4879)
- Qin Liu (ORCID: https://orcid.org/0000-0002-5416-1198)
- Shan Liu (ORCID: https://orcid.org/0000-0002-2192-0119)
- Hongyu Zhou
- Lin Shen (ORCID: https://orcid.org/0000-0002-0510-3733)
- Yu Zhang (ORCID: https://orcid.org/0000-0002-3463-9350)
- Jie Luo (ORCID: https://orcid.org/0000-0002-2070-9151)
- Xin‐Yuan Guan
- Beilei Liu (ORCID: https://orcid.org/0000-0002-0623-9093)
- Danyang Zheng (ORCID: https://orcid.org/0000-0003-3612-3793)
- Yuma Yang
- Ziyang Qi
Institutions
- Sun Yat-sen University (CN)
- City University of Hong Kong (HK)
- Sichuan Cancer Hospital (CN)
- University of Hong Kong - Shenzhen Hospital (CN)
- Sun Yat-sen University Cancer Center (CN)
- University of Hong Kong (HK)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-08-15
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102300
- Citations
- 4
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Guangdong Innovative and Entrepreneurial Research Team Program
- National Natural Science Foundation of China
- University Grants Committee
- Shenzhen Science and Technology Innovation Program