HDAC2 restrains IGF2BP1-associated m6A dysregulation in cervical cancer immunotherapy resistance

BACKGROUND: Cervical cancer (CC) immunotherapy resistance remains a critical clinical challenge. Although immune checkpoint blockade shows efficacy in subsets of patients, the epigenetic and post-transcriptional mechanisms driving resistance are poorly understood. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1), an m6A "reader," is implicated in tumor progression, but its role in CC immunotherapy resistance is undefined. The aim of this study was to elucidate the function of epigenetic regulator IGF2BP1 and HDAC2 in CC acquired immunotherapy resistance. METHODS: Multi-omics analysis of GEO/TCGA datasets identified immunotherapy response related genes. Functional validation employed siRNA knockdown, overexpression, in vitro co-culture assay treated with anti-PD-1. Molecular mechanisms were assessed via RIP/MeRIP-qPCR, ChIP-qPCR, and luciferase reporter experiments. RESULTS: IGF2BP1 was significantly upregulated in CC tissues and cell lines (HeLa, SiHa, CaSki, C-33A), correlating with poor survival (P < 0.001). IGF2BP1 knockdown suppressed proliferation and sensitized tumors to anti-PD-1 via enhancing CD8 ⁺ T cell infiltration and IFNγ secretion. Mechanistically, IGF2BP1 stabilized immune-response genes and stemness program genes (PD-L1, WNT4, POU5F1, MYC) via m6A-dependent mRNA processing. HDAC2 was differentially associated with PD-1 treatment response, suggesting a context-dependent function and potential value as an exploratory biomarker of immunotherapy responsiveness. HDAC2 repressed IGF2BP1 transcription by erasing H3K27ac marks at its promoter. Targeting above axis synergistically enhanced T cells activation and toxic function. CONCLUSIONS: We unveil an HDAC2/IGF2BP1/m6A axis is associated with cervical cancer immunotherapy resistance. HDAC2 loss derepresses IGF2BP1, stabilizing immunosuppressive and stemness-related transcripts via m6A modification. Targeting this axis partially restores PD-1 efficacy, providing a novel insight of cervical cancer immunotherapy resistance.