SLC39A13 Defines Myofibroblastic Activation and Immunosuppressive Tumor Microenvironment in Head and Neck Squamous...

Zinc transport plays a critical role in cellular signaling, but its function in the tumor microenvironment remains poorly understood. We aimed to investigate the role of zinc transporters in cancer-associated fibroblasts in head and neck squamous cell carcinoma. Single-cell RNA sequencing data were analyzed to evaluate zinc transporter expression across tumor cell populations, and bulk RNA sequencing of primary fibroblast cultures was used for validation. Clinical relevance was assessed using transcriptomic and survival data from a large patient cohort. We found that zinc transporter expression, particularly SLC39A13, was enriched in fibroblasts and strongly associated with myofibroblastic activation signatures, including extracellular matrix remodeling and TGFβ signaling. Fibroblasts with high SLC39A13 expression were linked to immunosuppressive tumor environments characterized by reduced cytotoxic T-cell infiltration and increased immunosuppressive cells. Clinically, SLC39A13 expression was associated with poor progression-free survival and remained an independent prognostic factor. These findings suggest that zinc transporter-mediated pathways play a key role in stromal activation and immune regulation, highlighting SLC39A13 as a potential therapeutic target in head and neck squamous cell carcinoma.