Transcriptional networks underlying tumour plasticity in small-cell lung cancer

Across human malignancies, the ability of cancer cells to switch states (plasticity) drives progression, metastasis, and therapy resistance 1-3. Here we investigated the transcriptional and epigenetic basis of plasticity in small-cell lung cancer (SCLC), an aggressive, treatment-refractory cancer 4, 5. SCLC tumours display plasticity along a neuroendocrine (NE) to nonNE axis; however, the trajectories of lineage transition and the gene regulatory network underlying it, remain poorly defined 6. Using single-cell multi-omics, we resolved distinct transcriptional SCLC cell states, including a previously unrecognised Intermediate state comprised of low-identity immunogenic SCLC cells that serve as an obligatory route in NE to nonNE lineage transition. Using single-cell gene expression and chromatin accessibility data, we next developed a Boolean Bayes model for transcription factor networks (BoBa-T) to predict regulators of SCLC cell states. We validated RORB as a novel gatekeeper of the NE state that represses the nonNE identity in SCLC. RORB inactivation drives NE cells into the Intermediate state, upregulates immunogenic programs, and inhibits tumour growth in immunocompetent hosts. Our work identifies a plastic, immunogenic waypoint for SCLC lineage switching and reveals strategies to target it therapeutically.