Integrated single-cell and spatial transcriptomics uncover the prognostic, epigenetic, and immunological roles of FANCC in low-grade glioma

Immunotherapy holds significant yet underexplored potential for low-grade glioma (LGG) treatment. We therefore interrogated the role of Fanconi Anemia Complementation Group C (FANCC) as a novel immune checkpoint regulator given its spatial correlation with tumor microenvironments and clinical associations with immunosuppressive markers. FANCC is implicated in various tumor progressions; its role in LGG remains unexplored. This study comprehensively investigates FANCC’s clinical significance, prognostic value, and molecular mechanisms driving LGG malignancy to identify novel therapeutic targets. FANCC overexpression in malignant single-cell subclusters correlated with advanced grade/recurrence. It independently predicted poor prognosis (KM log-rank <i>p</i> &lt; 0.001; multivariate Cox HR = 2.1, <i>p</i> &lt; 0.001). Spatial mapping revealed colocalization with immunosuppressive niches, supported by strong correlations with CD4+ T cells (<i>r</i> = 0.68) and M2 macrophages (<i>r</i> = 0.72), while inversely linking to M1 markers (<i>r</i> = −0.42). Immune checkpoints (PD-1/CTLA-4) showed significant co-expression (<i>r</i> &gt; 0.4). GSEA implicated FANCC in DNA replication and base excision repair (FDR &lt; 0.05), suggesting genomic instability drives progression. As the first-reported oncogenic driver in LGG, FANCC synergistically fuels progression via immune microenvironment reprogramming and DNA repair dysregulation, establishing its potential as a diagnostic/prognostic biomarker and therapeutic target.