Integrated Epigenetic and Transcriptomic Profiling Reveals Dynamic Regulatory Networks Driving Retinoblastoma Pathogenesis

Retinoblastoma (RB), the most aggressive pediatric intraocular malignancy, urgently requires mechanistic insights to overcome limitations of current clinical interventions. Through integrated single-cell multi-omics analysis, we constructed a comprehensive epigenetic-transcriptomic atlas of photoreceptor subpopulations in RB. Pseudotemporal trajectory analysis revealed the differentiation cascade from retinal progenitor cells (RPCs) to malignant cone-like tumor cells (Cone-T), orchestrated by dynamic regulation of tumor suppressors (FEZ1) and oncogenic drivers (CITED2) within the MAPK pathway. Notably, we identified three photoreceptor subtype-specific transcription factors (EBF1, SOX15, NFIL3) exhibiting concordant overexpression and chromatin accessibility. Cell-cell communication analysis uncovered PPIA-BSG ligand-receptor interactions potentially driving tumor progression, while drug screening prioritized nine therapeutic candidates targeting transitional proliferative photoreceptors (P-p). Our findings establish a mechanistic framework for photoreceptor transformation and provide actionable targets for precision therapies.