Dual Disruption of EGFR/PI3K Signaling: IGF2BP2 Targeting Reverses Anti-EGFR Resistance in CAFs-Infiltrated Oral Squamous Cell Carcinoma

RNA-binding proteins (RBPs) critically regulate post-transcriptional gene networks, yet their roles and mechanisms in oral squamous cell carcinoma (OSCC) remain underexplored. Dysregulated RBPs were identified through integrated analysis of RNA-seq and single-cell RNA-seq. The oncogenic functions of IGF2BP2 were evaluated through tissue microarrays, CCK-8, transwell assays, mouse xenografts, and <i>Igf2bp2</i>-deficient mouse models of tongue SCC (TSCC). Subsequently, we utilized RNA-seq, RIP-seq, RIP/MeRIP-qPCR, and dual-luciferase reporter assays to investigate IGF2BP2-target genes. Furthermore, cell co-culture system and mouse TSCC models were used to validate the therapeutic effect of the IGF2BP2 inhibitor. IGF2BP2 was the most markedly upregulated RBP in OSCC cells and cancer-associated fibroblasts (CAFs), correlating with unfavorable prognosis. IGF2BP2 deprivation significantly impaired human OSCC proliferation and metastasis, and delayed mouse TSCC onset. Mechanistically, IGF2BP2 stabilized EGFR and PIK3R1 mRNA via m6A-dependent interactions, thereby sustaining activation of the EGFR/PI3K/AKT oncogenic axis. Pharmacological inhibition of IGF2BP2 exhibited anti-OSCC efficacy in vivo and in vitro by concurrently suppressing EGFR and PI3K/AKT pathway activity, overcoming anti-EGFR resistance resulting from cell-intrinsic PI3K/AKT hyperactivation and CAF-secreted factors. Our findings identified IGF2BP2 as a master regulator of OSCC progression and a promising therapeutic target, offering an alternative strategy for OSCC patients suffering anti-EGFR resistance.