Work

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

Year: 2025

Type: article

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. • SOX4 is a master transcription regulator in NPC pathogenesis • NPC cells absorb zinc through the SOX4-ZIP14-zinc axis, enhancing malignant traits • Microenvironmental zinc deficiency leads to dysfunction of infiltrating CD8 + T cells • AAV-SOX4-RNAi intratumoral injection inhibits tumor growth and boosts CD8 + T cell response Yang et al. demonstrate that nasopharyngeal carcinoma (NPC)-specific SOX4 regulates zinc metabolism via ZIP14, promoting tumor growth and creating a zinc-deficient niche that impairs CD8 + T cell function, highlighting the SOX4-ZIP14-zinc axis as a potential therapeutic target for NPC treatment.

Source: Cell Reports Medicine

DOI: 10.1016/j.xcrm.2025.102300