BackgroundHead and neck squamous cell carcinoma (HNSCC) is a prevalent malignancy, with high mortality rate and unavailability of accurate therapies. However, its early prevention remains a challenge. In the purview of predictive, preventive, and personalized medicine (PPPM), it is paramount to identify novel and powerful biomarkers. CISD2 is a crucial regulator of iron homeostasis and reactive oxygen species (ROS). Recent studies showed that the NEET protein (NAF‐1) encoded by CISD2 is involved in regulating the proliferation and metastasis of tumor cells. Nevertheless, the prognostic value and immunological correlations of CISD2 remain unclear.MethodsBioinformatics analyses conducted utilizing data from comprehensive databases The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). All statistical evaluations were executed employing R software.ResultsOur investigation of biological function, enrichment pathway, and immune correlation revealed a discernable linkage between CISD2 and the immune response. Moreover, we found that the suppression of CISD2 is associated with immune cell infiltration and various immune signatures.ConclusionsThe present study successfully revealed the potential prognostic and biological function of CISD2 in HNSCC. High expression of CISD2 are linked to gender, race, grade, etc., can notably enhance the early detection, prognosis, and prediction for individuals afflicted with HNSCC.