Targeting PRPF19 suppresses lung cancer progression by abrogating cytokinesis and potentiating anti-tumor immunity

Lung cancer remains the leading cause of cancer-related mortality worldwide, highlighting the critical need to identify key oncogenic drivers and develop effective therapeutic strategies. Here, we demonstrate that pre-mRNA processing factor 19 (PRPF19) is significantly upregulated in lung cancer tissues and correlates with poor clinical prognosis. Mechanistically, PRPF19 mediates linear (M1-linked) ubiquitylation of Citron Kinase (CIT), which is essential for CIT midbody localization and successful cytokinesis; PRPF19 knockdown induces cytokinesis failure, cell cycle arrest, and impaired proliferation. In parallel, PRPF19 promotes lysosomal degradation of p65 via linear ubiquitylation, thereby suppressing NF-κB signaling and CXCL10 expression. PRPF19 knockdown stabilizes p65, elevates CXCL10, and enhances CD8 + T cell infiltration and anti-tumor immunity in a CXCL10/CXCR3-dependent manner. Collectively, our findings establish PRPF19 as a dual function regulator governing both cytokinesis and immune evasion in lung cancer, revealing a promising therapeutic target and providing mechanistic basis for novel treatment strategies.