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

Background: 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.

Objectives: 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.

Results: FANCC overexpression in malignant single-cell subclusters correlated with advanced grade/recurrence. It independently predicted poor prognosis (KM log-rank p < 0.001; multivariate Cox HR = 2.1, p < 0.001). Spatial mapping revealed colocalization with immunosuppressive niches, supported by strong correlations with CD4+ T cells (r = 0.68) and M2 macrophages (r = 0.72), while inversely linking to M1 markers (r = -0.42). Immune checkpoints (PD-1/CTLA-4) showed significant co-expression (r > 0.4). GSEA implicated FANCC in DNA replication and base excision repair (FDR < 0.05), suggesting genomic instability drives progression.

Conclusion: 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.