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  3. SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma

SOX4-ZIP14-zinc metabolism mediates oncogenesis and suppresses T cell immunity in nasopharyngeal carcinoma

  • Cell Rep Med. 2025 Aug 13:102300. doi: 10.1016/j.xcrm.2025.102300.
Yuma Yang 1,  Qin Liu 1,  Jie Luo 1,  Ziyang Qi 1,  Shanshan Li 2,  Lin Shen 2,  Jishi Li 2,  Xiaona Fang 3,  Jiao Huang 1,  Beilei Liu 4,  Shan Liu 5,  Hongyu Zhou 1,  Lu Bai 1,  Ching Ngar Wong 6,  Baifeng Zhang 6,  Danyang Zheng 6,  Yu Zhang 7,  Wei Dai 1,  Lanqi Gong 8,  Xin-Yuan Guan 9
Affiliations

Affiliations

  • 1 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 2 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 3 Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Tung Biomedical Sciences Centre, City University of Hong Kong, Hong Kong SAR, China.
  • 5 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Radiation Oncology, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, China.
  • 6 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 7 Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 8 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. Electronic address: lqgong94@hku.hk.
  • 9 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China; Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. Electronic address: xyguan@hku.hk.
PMID: 40818459 DOI: 10.1016/j.xcrm.2025.102300
Abstract

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+ 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.

Keywords

CD8(+) T cells; LCK signaling; SOX4; ZIP14; immune resistance; nasopharyngeal carcinoma; oncogenesis; tumor microenvironment; zinc metabolism.

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