Organoid-based modeling unveils Dnmt3a-driven epigenetic regulation of phenotypic plasticity in small cell lung cancer

Small cell lung cancer (SCLC) harbors pronounced intratumoral heterogeneity, yet epigenetic drivers of subtype plasticity remain poorly understood. Herein, we established paired neuroendocrine (NE)-high and NE-low SCLC organoids from pulmonary neuroendocrine cells (PNECs)-specific Trp53/Rb1/Pten-triple knockout mice. NE-high organoids developed prominent axon-like protrusions, while NE-low counterparts exhibited cystic structures. Both subtypes maintained primary tumor genetics and tumorigenicity. Transcriptomics revealed NE-high enrichment of neuronal programs versus innate immune pathway upregulation in NE-low organoids. Mechanistically, Polycomb repressive complex 2 (PRC2)-mediated H3K27me3 enrichment in NE-low organoids suppressed Dnmt3a, causing global DNA hypomethylation that reactivated endogenous retroviruses (ERVs), triggering cytosolic double-stranded RNA (dsRNA) accumulation and consequent antiviral interferon response. Notably, Carm1 stabilized Dnmt3a via transient methylation. Targeting Dnmt3a or Carm1 in NE-high organoids drove their transition to a NE-low state with ERV de-repression. Collectively, these findings establish a PRC2/CARM1/DNMT3A axis orchestrating SCLC plasticity, identifying DNA methyltransferase inhibition as a potential therapeutic strategy targeting SCLC heterogeneity and immunosuppression.