UHRF1 drives subtype-independent aggressiveness and immune evasion in small cell lung cancer through PRC2 interactions.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine (NE) carcinoma characterized by early metastasis and an immune-cold microenvironment. We show that UHRF1, a chromatin-associated effector of RB1/E2F signaling, promotes SCLC growth and metastasis across major molecular subtypes. Using human SCLC cell lines, orthotopic and intracardiac xenografts, and genetically engineered mouse models, we found that loss of UHRF1 reduces proliferation, invasion, tumor burden, and metastasis while reprogramming tumors away from NE states toward an inflamed transcriptional program. UHRF1-deficient tumors upregulate chemokines and exhibit increased infiltration of CD8+ T cells and myeloid populations. Mechanistically, UHRF1 interacts with PRC2 to reinforce NE lineage programs and suppress inflammatory gene expression. UHRF1 loss derepresses DNA-methylation-silenced tumor antigens, including MAGE-A4, highlighting a potential vulnerability that could be leveraged therapeutically. Together, these findings connect RB1 loss with chromatin repression, lineage control, and immune exclusion, highlighting UHRF1-dependent repression as a therapeutic vulnerability in SCLC.