Cellular Identity Crisis: RD3 Loss Fuels Plasticity and Immune Silence in Progressive Neuroblastoma

Therapy-resistant neuroblastoma (NB) reflects a lethal convergence of cellular plasticity and immune escape, yet the molecular drivers remain elusive. Here, we identify retinal degeneration protein 3 (RD3) as a master regulator of NB lineage fidelity and tumor immunogenicity. RD3 loss, induced by therapy, triggers a reprogramming cascade involving epithelial-mesenchymal transition, pluripotency circuitry, and cancer stem cell enrichment. Mechanistically, RD3 binds to and regulates the promoter activity of SOX2, NANOG, and OCT3/4, as well as regulates the transcription of EMT factors. Concurrently, RD3 deficiency disrupts antigen presentation (MHC I/II, β2M), upregulates immune checkpoints (PDL1, CD276), and activates immune-suppressive signaling (CD24, CD73, A2AR), fostering an immune-silent microenvironment. RD3 restoration reverses these transitions, reinstating epithelial identity, differentiation, and immune surveillance. In-vivo, RD3 modulates immune cell infiltration, activation, and tumor clearance. Mechanistically, RD3 governs a self-reinforcing axis of cellular identity and immunoediting (by regulating T-cell cytokine release, activation, and cytotoxic function), positioning it as a critical checkpoint in NB evolution. These findings establish RD3 as a dual-function molecular switch and nominate RD3-targeted strategies to re-sensitize high-risk NB to immunotherapy.