ABSTRACT 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.
Subramanian et al. (Sat,) studied this question.
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