IGF2BP3 promotes immune evasion and predicts poor prognosis in head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and limited prognostic biomarkers. The RNA-binding protein insulin-like growth factor 2 messenger RNA-binding protein 3 (IGF2BP3) recognizes N6-methyladenosine (m6A) and promotes tumor progression in multiple cancers, but its prognostic value and immunological role in HNSCC remain unclear. This study aims to explore the role of IGF2BP3 in the pathogenesis of HNSCC, investigate its potential as a reliable diagnostic and prognostic biomarker, and assess its applicability as a novel immunotherapeutic target, with the goal of improving clinical outcomes for patients with HNSCC.

IGF2BP3 expression and its association with clinicopathological features and survival were analyzed using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) datasets. Receiver operating characteristic (ROC) curves and multivariate Cox regression were used to evaluate its diagnostic and prognostic value. Co-expressed genes were identified via cBioPortal, followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses. Immune cell infiltration was estimated using single-sample gene set enrichment analysis (ssGSEA). The functional role of IGF2BP3 was validated in SCC-25 cells using small interfering RNA (siRNA) knockdown, Cell Counting Kit-8 (CCK-8) proliferation assays, wound-healing assays, and Transwell migration/invasion assays.

IGF2BP3 messenger RNA (mRNA) and protein were significantly upregulated in HNSCC tissues compared with normal controls (P<0.001). ROC analysis yielded an area under the curve (AUC) of 0.809 [95% confidence interval (CI): 0.753-0.866], indicating good diagnostic performance. High IGF2BP3 expression was associated with advanced clinical stage and independently predicted worse overall survival in multivariate Cox analysis. Enrichment analyses suggested that IGF2BP3-related genes were involved in metabolic reprogramming and RNA-binding protein networks. IGF2BP3 expression correlated positively with Th2 cells and negatively with cytotoxic T and natural killer (NK) cells, indicating an immunosuppressive tumor microenvironment. Functionally, IGF2BP3 knockdown significantly inhibited SCC-25 cell proliferation, migration, and invasion in vitro (all P<0.01).

IGF2BP3 is overexpressed in HNSCC and is associated with advanced stage, unfavorable prognosis, and an immunosuppressive immune landscape. IGF2BP3 represents a promising diagnostic and prognostic biomarker and may constitute a potential therapeutic target in HNSCC.