SOX4 is a master regulator of initiation, progression and immune evasion in nasopharyngeal carcinoma via disruption of zinc homeostasis

Abstract

Nasopharyngeal carcinoma (NPC) is a relatively rare squamous malignancy, with distinct epidemiological features primarily observed in East Asia, Southeast Asia, and North Africa. NPC is characterized as an inflammatory cancer with dense immune cell infiltration, yet medical treatment, including immunotherapy, has not yet achieved satisfactory efficacy due to treatment failure caused by distant metastasis, local recurrence, and drug resistance. The complexity of the NPC immune microenvironment has hindered a comprehensive understanding of immune cell phenotype, function, and interaction with tumor cells, making it challenging to identify effective therapeutic targets. Therefore, a more detailed study of the NPC immune microenvironment is required to uncover improved therapeutic strategies. Based on single-cell RNA sequencing (scRNA-seq) analysis and bulk transcriptome data validation, we observed specifically and significantly high expression levels of SRY-Box transcription factor 4 (SOX4), an essential developmental transcription factor, in NPC cells compared to infiltrating immune and stromal cells. In our study, we found the upregulation of SOX4 contributed to tumor growth, distant metastasis, and stemness maintenance. More interestingly, we noticed NPC cells could affect infiltrated CD8+ T cells function via competitive zinc deprivation. During this process, the overexpressed SOX4 promoted the upregulation of downstream target SLC39A14 (ZIP14), which is the zinc transporter protein, to uptake excessive zinc from the extracellular microenvironment, as a result, leading to zinc competitive deprivation in infiltrated T cells. T-cell zinc competitive deprivation inhibited TCR signaling, impeded T-cell activation, and caused CD8+ T cytotoxicity failure, ultimately resulting in NPC immune evasion. This study first demonstrated that the SOX4-ZIP14-zinc axis played a crucial role in both the induction of tumor progression and the suppression of the immune response in NPC. Blockage of the axis represented a novel therapeutic strategy for treating patients with NPC, which could potentially synergize with PD-1/PD-L1 blockers to overcome immunosuppressive signals in the NPC TME and improve the clinical outcome.