ObjectiveThis study aims to explore the predictive value of SLC25A17 in the prognosis and tumor microenvironment (TME) of patients with head and neck squamous cell carcinoma (HNSCC) and to provide ideas for individual clinical treatment.MethodsA pancancer analysis of the differential expression of SLC25A17 among different tumors was first conducted via the TIMER 2.0 database. Subsequently, the expression of SLC25A17 and related clinical information of HNSCC patients were obtained from the TCGA database, and patients were divided into two groups according to the median value of SLC25A17 expression. K‒M survival analysis was conducted to compare the overall survival (OS) and progression-free survival (PFS) between the groups. The Wilcoxon test was used to compare the distribution of SLC25A17 in different clinical characteristics, and univariate Cox and multivariate Cox analyses were performed to analyze independent prognostic factors to establish a predictive nomogram. Calibration curves were generated to verify the reliability of predicting 1-year, 3-year and 5-year survival rates and another cohort (GSE65858) was used for external validation. Gene set enrichment analysis was conducted to compare the enriched pathways, and the immune microenvironment was assessed using the CIBERSORT and estimate packages. Furthermore, the expression levels of SLC25A17 in immune cells were also analyzed with single-cell RNA-seq via the TISCH. Moreover, the immunotherapeutic response and chemotherapy drug sensitivity were compared between the two groups to guide precise treatment. The TIDE database was applied to predict the possibility of immune escape in the TCGA-HNSC cohort.ResultsCompared with normal samples, the expression of SLC25A17 was much higher in HNSCC tumor samples. For patients with high SLC25A17 expression, the OS and PFS were shorter than those with low SLC25A17 expression, indicating a worse prognosis. The expression of SLC25A17 varied in different clinical features. Univariate Cox and multivariate COX analyses showed that SLC25A17, age, and lymph node metastasis are independent prognostic risk factors for HNSCC, and the survival prediction model based on these factors had reliable predictive value. Patients in the low-expression group exhibited more immune cell infiltration, higher TME scores, higher IPS scores and lower TIDE scores than those in the high-expression groups, suggesting better immunotherapeutic response with lower SLC25A17 expression. Moreover, patients in the high-expression group were more sensitive to chemotherapy.ConclusionsSLC25A17 can effectively predict the prognosis of HNSCC patients and could be a precise individual-targeted indicator for the treatment of HNSCC patients.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12859-023-05399-6.